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Atopic Dermatitis — Peeling the Onion

A useful and thorough overview of the latest findings on atopic dermatitis and recommendations for clinicians

The July 2006 issue of the Journal of Allergy and Clinical Immunology presents several valuable reviews of atopic dermatitis (AD). With an AD incidence of about 17% in schoolchildren in the U.S., and with new data providing insights into the molecular basis for the genetic predisposition to atopy, it is a propitious time for this comprehensive set of reviews. The information covered in this summary is highly selective — the entire set of articles should be read to appreciate the richness and complexity of the topic. Several of the authors and some of the studies had drug company support.

THE PATIENT’S PERSPECTIVE

The International Study of Life with Atopic Eczema (ISOLATE) investigators evaluated the effect of moderate-to-severe AD on the lives of 2002 patients in eight countries.1 Patients with a flare in the previous 6 months were eligible to undergo standardized phone interviews. Of these, 55% were cared for by dermatologists and 39% by pediatricians. They experienced, on average, 9 flares per year, which lasted an average of 15 days each. It took an average of 1 week for care to be instituted, suggesting room for improvement in patient care. During flares, 86% of patients avoided everyday activity, 55% worried about the next flare, and 43% were concerned about appearing in public; 39% of affected children (age range, 8–17 years) reported being bullied in school because of AD. Eighty-four percent of patients and caretakers were unaware of the existence of patient care groups. Although AD is a chronic disease, 77% of patients and 74% of caregivers did not feel confident to manage the disease without a physician. Detailed subanalyses of the data from this study will be published in the future.

The Role of Genetics2,3,4 AD has a much higher concordance in monozygotic than in dizygotic twins, which is the hallmark of genetic disease in classic twin studies. Attempts to understand the molecular basis of AD have focused on molecules of the immune system and the epidermis. Candidate-gene studies have pointed to genes related to serine protease inhibitors (SPINK5 — the gene in Netherton syndrome), toll receptors, chymases, and various cytokines. Filaggrin loss-of-function mutations have been strongly associated with AD in studies of several European populations. Deficient filaggrin synthesis produces cell envelopes lacking the filaggrin molecule, and perhaps more importantly, reductions in free amino acids that maintain water content in the stratum corneum. In addition to molecular defects in the barrier, AD is also associated with gross impairment of epidermal integrity. Corneodesmosomes are part of the adhesive system that maintains stratum corneum structure, and defects in this component and other supports of epidermal integrity and barrier function play a role in AD. It remains to be determined if all epidermal defects lead to a common pathway and whether these defects increase percutaneous sensitization. Because epidermal barrier impairment also occurs in diseases that are not associated with AD (e.g., psoriasis and forms of epidermolysis bullosa and ichthyosis), the link between barrier impairment and AD is probably more complex than is usually proposed.

The Role of the Environment5 After systematically reviewing the literature, epidemiologists question three common assumptions about AD: the contributory role of allergic sensitization, the concept of the atopic march (progression from eczema to asthma with age), and the predisposing role of reduced bacterial infections in early childhood (the hygiene hypothesis).

The Roles of Infection and Immunology6,7,8 Infection, both bacterial (Staphylococcus aureus) and herpetic, is associated with alterations in the innate immune system and defects in skin-produced antibacterial peptides (cathelicidins and beta defensin) and interleukin-1. Staphylococcus colonization and infection are especially important because staphylococcus exfoliative toxin cleaves Desmoglein1 and disrupts desmosomal structure. In addition, the S. aureus superantigen induces a competitive glucocorticoid receptor that interferes with the normal binding of corticosteroids and their therapeutic effect. Defects in the immune system are implicated in AD in a number of different ways.

The Role of the Vasculature9 Patients with AD have abnormal vasoconstrictor responses to mechanical pressure or acetylcholine (white dermographism) and also have peripheral vasoconstriction. Vascular innervation, neurotrophins, adhesion molecules, and cytokines all have roles in endothelial and vascular response. Multiple inflammatory mediators are part of the vascular response. This area, relatively neglected in the past, is now ripe for further study.

What Should Physicians Do? The Consensus Statement10 The European Academy of Allergology and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology have produced an important consensus statement on AD. They review the basic biology of the disease and evaluate such triggers as stress, allergens, Malassezia furfur and other infections, and IgE antibodies. Food hypersensitivity is considered a complicating or inciting factor, especially in younger patients. Inhalant and contact allergy are considered. A useful stepwise therapeutic ladder is presented. It begins with trigger avoidance and the use of hydration and emollients. It progresses through increasingly potent topical steroids and topical calcineurin inhibitors for patients older than 2 years, and arrives at UV light, cyclosporin, and azathioprine for the most severely affected. The authors discuss the need for patient education and empowerment. Primary-prevention models and studies of new monoclonal antibodies are still in early stages, and enthusiasm should be tempered until enough data have been assembled for meaningful meta-analysis.

Comment: These articles present a state-of-the-art overview of atopic dermatitis. Research into how immune mechanisms and epidermis are related to clinical disease will continue at its current feverish pace. The role of environmental factors will have to be delimited as precisely as the role of genetic variables if our understanding is to advance. The eventual model of AD will be complex, reflecting the interplay of multiple variables. Physicians and patients looking for simple answers may be disappointed.

— Lowell A. Goldsmith, MD, MPH

Published in Journal Watch Dermatology August 4, 2006

Citation(s):

1. Zuberbier T et al. Patient perspectives on the management of atopic dermatitis. J Allergy Clin Immunol 2006 Jul; 118:226-32.

2. Cork MJ et al. New perspectives on epidermal barrier dysfunction in atopic dermatitis: Gene-environment interactions. J Allergy Clin Immunol 2006 Jul; 118:3-21.

3. Morar N et al. The genetics of atopic dermatitis. J Allergy Clin Immunol 2006 Jul; 118:24-34.

4. Weidinger S et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006 Jul; 118:214-9.

5. Williams H and Flohr C. How epidemiology has challenged 3 prevailing concepts about atopic dermatitis. J Allergy Clin Immunol 2006 Jul; 118:209-13.

6. Boguniewicz M et al. Atopic dermatitis. J Allergy Clin Immunol 2006 Jul; 118:40-3.

7. Homey B et al. Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 2006 Jul; 118:178-89.

8. McGirt LY and Beck LA. Innate immune defects in atopic dermatitis. J Allergy Clin Immunol 2006 Jul; 118:202-8.

9. Steinhoff M et al. Role of vasculature in atopic dermatitis. J Allergy Clin Immunol 2006 Jul; 118:190-7.

10. Akdis CA et al. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. J Allergy Clin Immunol 2006 Jul; 118:152-69.

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Copyright © 2006. Massachusetts Medical Society. All rights reserved.