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Meeting the Challenge of Atopic Dermatitis in Infancy and Childhood

Current Understanding in the Epidemiology and Pathophysiology of Atopic Dermatitis

Epidemiology
Mark Boguniewicz, MD, Professor in the Division of Pediatric Allergy and Immunology, Department of Pediatrics at National Jewish Medical and Research Center in Denver, CO introduced the audience to atopic dermatitis (AD) by stating that AD is a chronic, relapsing, highly pruritic, inflammatory skin disease that frequently precedes the development of asthma and/or allergic rhinoconjunctivitis.

The prevalence of AD varies with each study, based on location, AD criteria, and age. For example, in Japan, AD occurs in 24% of 5-6 year olds and 11% of 16-18 year olds (Acta Derm Venereol 1998;78:293-294). Comparable values are seen elsewhere with up to 17% of school-aged children in Oregon affected and more importantly, the prevalence of AD appears to be increasing. In the Japanese study, “the prevalence of AD in 9- to 12-year-old children was two times, and in 18-year-old adolescents, five times as high as in similar age groups examined 20 years ago,” said Dr. Boguniewicz (Acta Derm Venereol 1998;78:293-294). Similar increases have been seen in Scandinavian countries when comparing data from different decades (Clin Exp Allergy 25:815-819, 1995, Immunol Allergy Clinics N Am 2002;22:1-24).

Epidemiological studies have also confirmed a correlation between AD and asthma and allergic rhinoconjunctivitis. “AD is often the first manifestation of the atopic diasthesis and approximately 50% of patients will go on to develop asthma and/or allergic rhinitis,” said Dr. Boguniewicz.

Pathophysiology
The pathophysiology of AD is not completely understood but a number of studies suggest that AD results from a bone marrow-derived cell dysfunction rather than a constitutive skin defect. Systemic abnormalities observed in AD include: expansion of IL-4-, IL-5- and IL-13- secreting Th2-type cells; decreased numbers of IFN-gamma-secreting Th1-type cells; increased serum IgE levels and increased numbers of circulating eosinophils.

Recent studies have focused on the high levels of colonization by S. aureus in AD patients and Dr. Boguniewicz pointed out that this may be associated with decreased expression of antimicrobial peptides such as human b-defensin 2, possibly due to suppressive effects of IL-4 and IL-13 (N Engl J Med 2002; 347:1151-1160). Furthermore, S. aureus may cause exacerbations of AD and contribute to chronic inflammation by secreting toxins with superantigenic properties leading to massive proliferation of T cells and activation of pro-inflammatory pathways (Semin Cutan Med Surg 2001;20:217-225).

In addition, superantigens can also augment specific IgE response to conventional allergens and induce cortico-steroid insensitivity. These superantigens can induce erythema and induration when applied directly to the skin, and infiltrating T cells show selective expansion to these specific toxins. Dr. Boguniewicz added, “work done at our center a few years back showed that patients can make IgE specific to the superantigens that are being secreted on their skin (J Clin Invest 1993; 92:1374-80) and thus, you can get involvement of mast cells and basophils directly through such interactions,” adding, “our colleagues in Germany have shown that it is the toxin-specific IgE that correlates with disease severity rather than total serum IgE levels” (J Allergy Clin Immunol 1999;103:119-124).

Concluding Remarks
AD may be due to a complex interaction of genetic and environmental factors. Dr. Boguniewicz concluded his lecture by stating that new treatments for AD should be evaluated by looking at their impact on the natural history of the disease, and also how they may impact the development of asthma and allergies.

The Challenge of Treating Atopic Dermatitis in Infants

Atopic dermatitis (AD) is different in infants than it is in older children. “In infancy, we really see these symmetrically located changes in the skin of the face, neck, and/or upper torso, and typically the extensor surfaces of the arms and legs are affected,” said Adelaide Hebert, MD, Professor of Dermatology and Pediatrics and Vice Chairman of the Department of Dermatology at the University of Texas, Houston, TX.

A major factor that makes infants unique is the larger skin surface area to body weight ratio seen in infants compared to adults or older children. This also makes treatment options different. “These children, because of the greater body surface area to mass, will have a greater susceptibility to developing HPA axis suppression if topical steroids are applied in high concentrations or many times a day or over long periods of time,” said Dr. Hebert. Fortunately, by the third year of life, there is a significant decline in AD (~26%). However, “without remission, some of the children will go on to have progressive and severe disease,” said Dr. Hebert, adding, “and the extent may be related to the initial severity we see in infancy.”

One of the key steps to treating the infant with AD is parent education. A well- informed parent can properly identify AD, provide early intervention, and cope with its challenges. Two helpful ways to educate parents include a 1-800 number sponsored by the National Eczema Association and a thoughtful, humorous book written by Vicki Iovine (author of Girlfriend’s Guide to Pregnancy) and sponsored by Novartis. The book is entitled The Girlfriend’s Guide to Pediatric Eczema and is available for free by calling 1-866-545-6711.

Treatment Phototherapy
“We do quite a bit of phototherapy in my Dermatology clinic for patients with atopic dermatitis,” said Dr. Hebert, adding “it does three things: reduces insensible water loss; reduces staphylococcal colonization of the skin; and decreases pruritus.” Phototherapy is a very valuable therapy to use in conjunction with other modalities.

Emollients
Emollients are safe, cost-effective, and readily available treatments that are fairly easy to use for any patient. One new physiologic emollient that has proven effective in infants is the ceramide-based emollient, Triceram, that can be applied prior to a topical steroid to enhance the steroid getting into the skin. It is an over-the-counter product and can be bought in local cosmetic stores. A recent report by Dr. Chamlin et al. (Arch Dermatol 2001;137:1110-112) showed Triceram improved AD severity in 19 of 21 children with moderate to severe AD. “The severity score of 19 of the 21 children dropped at 3 weeks to a significant level, and it was found to be even more significant at 6 weeks,” said Dr. Hebert, adding, “two of the 21 patients who did not improve proved to have skin infections.” Furthermore, the 19 children that improved had a reduction in trans-epidermal water loss and their skin was less dry.

Topical steroids
There are several topical steroids available for AD. To illustrate their safety and efficacy, Dr. Hebert used the example of Cutivate (fluticasone propionate) which was recently investigated by Dr. Hebert’s clinical trial team in Houston. “Our data showed that Cutivate was safe and effective in cream formulation for children from 3 months and up,” said Dr. Hebert. In another trial, the efficacy and safety of fluticasone propionate cream (BID 3-4 weeks) in children with at least 55% body surface area was examined and it was found that the children did very well with no adrenal suppression ( J Am Acad Dermatol 2002;46:387-393). “Fortunately, Cutivate has a very low potential for skin atrophy and has a very high lipophilicity which means it gets into the skin and stays in the skin, it doesn’t go into the systemic circulation,” said Dr. Hebert, adding, “it has a high selectivity and affinity for the glucocorticoid receptor and it has rapid metabolism and clearance, and this is what we want in pediatric patients.”

Dr. Hebert prefers intermittent use of low potency steroids for infants (i.e., 2 weeks on and 2 weeks off). Unfortunately, there are side effects in using topical steroids. Glaucoma, Cushing’s disease, and HPA axis suppression are all concerns when applying steroids to children. For example, in one study with Diprolene, 10% of the patients (7 of 67 children) developed HPA axis problems. A survey of parents published in the British Journal of Dermatology found thinning of the skin, nonspecific long-term effects, and effects on growth as major concerns the parents had when using topical steroids on their children.

Moisture
Wet-wrap dressings are a cheap and effective way to keep children warm while allowing topical steroid creams to enter the skin. Dr. Hebert admitted, “we often do this in our Dermatology clinic in lieu of admitting a patient to the hospital,” adding, “it’s certainly cost-effective, it allows the family to stay intact, and it gives the patient a great deal of relief.”

Dr. Hebert also stressed the benefits of bathing. Most children enjoy baths and a 20-minute soaking in warm water allows the skin to reach its maximum hydration. After drying off (pat dry), the medications are applied to the affected areas.

New Possibilities for Treating Atopic Dermatitis in Children and Adults

In a continuation of Dr. Hebert’s presentation, Moise Levy, MD, Professor of Dermatology and Pediatrics and the Chief of Pediatric Dermatology at Baylor College of Medicine stated that one of the greatest concerns with traditional topical corticosteroid treatment are the side effects. This is especially true in children. Therefore, Dr. Levy discussed the safety and efficacy of newer alternatives for treating AD.

To date, there are two steroid-free topical immunosuppressive agents available: Protopic (tacrolimus) and Elidel (pimecrolimus). Both are cell-selective cytokine inhibitors and very effective anti-inflammatory agents. Chemically, these two drugs are very similar and although a direct comparison of the two drugs for safety and efficacy has yet to be performed, Dr. Levy provided the audience with some of the clinical data available on these two medications for the treatment of AD.

The first drug, tacrolimus, has been available for over a year and clinical trials have found it to be effective in reducing AD symptoms. Common side effects with tacrolimus are pruritus and skin burning. As many as 20-30% of patients experience these events but they are generally short duration (5-7 days). These side effects can be minimized if the families and patients are taught to apply the cream to dry instead of recently moist skin.

“Now what about pimecrolimus?” asked Dr. Levy. In the 6- week trial, 403 patients with mild to moderate AD were analyzed (J Am Acad Dermatol 2002; 46:495-504). One method used to assess efficacy is the Eczema Area and Severity Index (EASI) score which was a compilation of disease severity, regional sites of involvement, proportion of involvement, and different areas of the body. Other outcomes measured included the Investigator’s Global Assessment (IGA), severity of pruritus scores, and discontinuation.

Looking at EASI scores, there was a “very prompt and continued decrease in this EASI score, again reflective of clinical improvement in signs and severity of the disease,” stated Dr. Levy. IGA scores and pruritus scores showed similar improvements. Dr. Levy said, “a remarkable feature of this drug, I think, is a very prompt response to improving the pruritus,” adding, “this is something that all the families remark to us about.”

In regard to discontinuation, Dr. Levy said, “I can tell you that there were certainly very few discontinuations in the treatment arm of the study,” adding, “if you focus on the issue of unsatisfactory therapeutic effect under the study arm of the study, it certainly was not a predominant reason for discontinuation compared to vehicle alone.” Adverse events were consistent between the vehicle group and the study group and “most of the adverse effects were mild to moderate and were felt to be unrelated to treatment,” said Dr. Levy.

Long- term Treatment
Data on long- term treatment is limited since both drugs are fairly new. However, in a one year study with tacrolimus, it was observed that most side effects occur at the onset of treatment and subside over time. Dr. Levy said, “as with the short-term studies, the predominant problem with this medication is again, the skin burning or pruritus, and this decreased after day five to eight, certainly during the first week of application of the medication.” (J Am Acad Dermatol 2001;44:S58-S64). In a 3-year study involving tacrolimus for the treatment of AD, similar results were observed and Dr. Levy said, “again, a very steady and obvious decline in both body surface area of involvement in these patients, as well as in their measurable scores of evaluation” (Semin Cutan Med Surg 2001;20:250-259).

In regard to pimecrolimus, there is one long- term study that included 251 infants aged 3 to 23 months with AD and found the incidence of flares to be significantly lower in the pimecrolimus treated group compared to placebo over a 6- and 12-month period ( J Allergy Clin Immunol 2002;110:277-284). Further-more, Dr. Levy said “over the long-term phase of the investigations with pimecrolimus, as with the short-term data, the incidence of adverse effects were certainly comparable between the control group of patients and the study patients themselves.” In another long- term study Wahn et al (Pediatrics 2002;110:e2) examined the efficacy and safety of pimecrolimus in AD patients (mild, moderate, and severe: n = 713) for up to 12 months and found pimecrolimus to reduce AD flares in all patients and found patients required less need for topical cortico-steroid therapy. As in the other studies, the authors reported that pimecrolimus was well tolerated and was effective in preventing progression to flares in more than half of the patients and thereby reducing or eliminating the need for topical steroids.

Concluding Remarks
In most practices, an emollient is used for AD and at the first sign of pruritus or inflammation, a topical steroid is added. When considering the use of pimecrolimus or tacrolimus, every patient should still receive an emollient whether their disease shows inflammation or not but at the first sign of inflammation, pimecrolimus or tacrolimus can be used instead of a topical steroid. Dr. Levy cautioned however that if the patient experiences a flare, a topical corticosteroid can then be introduced to manage that particular complication.

In summary, the topical immunosuppressive agents, particularly pimecrolimus, have been shown to successfully reduce signs and symptoms of the AD, particularly its pruritus symptoms. Dr. Levy said, “it’s important that the drug be instituted at the earliest signs of inflammation, when pruritus or erythema begins.” Long-term studies up to one year show it is safe over a large body surface area and “it’s not been seen to be associated with any problem in regards to contact sensitization, photoallergy, or phototoxicity,” said Dr. Levy. As a cautionary note, Dr. Levy said “they are not applicable to every patient in every instance and certainly, at least in my mind, not for use in managing acute flares of bad dermatitis.”

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