Atopic dermatitis.

Abstract: Atopic dermatitis is a common, chronic skin condition characterized by xerosis, pruritus, and inflammation. Numerous factors place individuals at increased risk for developing this disease. T-helper cells and their cytokines, in addition to immunoglobulin E and eosinophils, play a major role in the pathogenesis of atopic dermatitis. Various hypotheses including the "hygiene hypothesis" and the "keratinocyte apoptosis hypothesis" have been proposed. Diagnosis is based on clinical criteria rather than objective testing. Allergic reactions to several triggers including foods may exacerbate symptoms. Treatment for atopic dermatitis consists of avoidance of triggers and administration of emollients, steroids, and topical immune response modifiers such as tacrolimus. Further research is necessary to better understand this disease.

Key Words: atopy patch test, emollients, food allergy, interleukins, keratinocytes, radioallergosorbent test, xerosis

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Atopic dermatitis (AD) is a chronic inflammatory skin condition that affects millions of individuals worldwide. The prevalence of atopic dermatitis has increased during the past 20 to 30 years, such that its lifetime prevalence is estimated at 10 to 15%. (1) Atopic dermatitis is characterized predominantly by varying degrees of dry skin (ie, xerosis) and pruritus. It is an "itch that rashes," unlike contact dermatitis, in which the rash appears before the itch. Pruritus leads to scratching, which can result in skin changes such as lichenification, excoriation, and breakdown of the skin barrier, leading to infection. (2)

Acute atopic dermatitis presents as erythematous patches, papules, plaques, and excoriation secondary to scratching. Chronic lesions have the same characteristics, with the addition of lichenification, fissures, and occasional alopecia. (3) Distribution is dependent on the age of the patient. In adults, flexural areas (Fig. 1), the front and sides of the neck, face, and wrists, and the dorsal areas of the hands and feet are the most commonly affected areas. Severe atopic dermatitis may be generalized. Infantile eczema predominantly involves the extensor surfaces of the arms and legs, the face, and the trunk because they can easily be reached to scratch. (4) Scaling, exudate, and fissures are also common findings in infants. Childhood atopic dermatitis has papular lichenified plaques, erosions, and crusts.

Several sets of diagnostic criteria for atopic dermatitis have been proposed. The Hanifin-Rajka diagnostic criteria for childhood atopic dermatitis require at least three major features for the diagnosis of AD (Table 1). (5) These features include pruritus, typical skin appearance and pattern of distribution, family or personal history of atopy, and chronic dermatitis in addition to at least three minor features. These criteria were revised in 1990 by a group of physicians in the United Kingdom to provide more standardized guidelines and less subjective diagnostic criteria to be used in epidemiologic studies. (5), (6)

Epidemiology

Risk factors for developing AD are multifactorial, consisting of both environmental and genetic influences. Approximately 80% of patients develop symptoms by age 5 to 7 years. (5) Many children develop manifestations of AD in early infancy, with symptoms and prevalence diminishing by young adulthood. Girls have a slight preponderance over boys in developing the disease. Those who have a family or personal history of atopic disease (asthma, allergic rhinitis, or atopic dermatitis) seem to be at highest risk. Atopy reflects the genetic propensity to make immunoglobulin (Ig) E rather than IgG to glycoprotein allergens.

Twin studies show a higher concordance among monozygotic twins (85%) than among dizygotic twins (21%). Maternal more than paternal history of atopy seems to contribute to the predisposition to the development of AD. There is an inverse relationship between the number of siblings in a family and the prevalence of AD. (4) Some supporters of the hygiene hypothesis propose that children from families with multiple siblings are protected from developing AD because of exposure to an increased number of infections in early childhood. (6)

[FIGURE 1 OMITTED]

In addition to genetic factors, environmental factors contribute to the prevalence of AD. A higher prevalence is found in higher socioeconomic classes and in more developed regions. Geographically, AD seems to have an increased prevalence in areas of increased environmental pollution and irritants. When individuals move from rural regions with a low prevalence of AD to urban regions with a westernized lifestyle, the prevalence of AD in these people becomes similar to that of natives over time. (5), (6)

Pathogenesis

Acute atopic dermatitis is associated with a cutaneous inflammatory response resembling that in the airways of patients with allergic rhinitis and asthma. T-cells, mainly of the CD4 lineage, are present in large numbers in skin lesions of AD. (7) Moreover, patients with atopic dermatitis have an increased percentage of activated cutaneous lymphocyte-associated antigen (CLA)-bearing T-cells both in the circulation and locally in dermal lesions. When these [CD4.sup.+][CLA.sup.+] T-cells are activated, cytokines are released into the serum and skin, promoting allergic inflammation. (8) The T-helper 2 (Th2) cytokine pattern predominates in acute atopic dermatitis, whereas a Thl pattern is present in chronic atopic dermatitis. (7), (9)

The cytokines released by Th2 cells upregulate antigen-presenting cells with IgE receptors. Among these antigen-presenting cells are cutaneous Langerhans cells and dendritic epidermal cells. These cells possess the Fc[euro]RI receptor, which has a high affinity for IgE. The upregulation of Fc[euro]RI on dendritic cells has been identified in AD lesions. (9), (10) The chemokine CCR3 is produced by Th2 lymphocytes and facilitates the migration of eosinophils, which are found in the lesional skin of patients with AD. (8), (11)

Some have hypothesized that both Th2 and Th1 cytokines play a key role in the pathogenesis of AD. These investigations suggest that on activation of Th1 cells, interferon-[gamma] is released, which upregulates the Fas ligand on keratinocytes. This upregulation allows the keratinocytes to be more susceptible to cell death (apoptosis). When this occurs, there is a loss of cohesion among keratinocytes in the epidermis, and fluid from the dermis moves into the epidermis, resulting in transepidermal fluid loss. This phenomenon is known as spongiosis and is a hallmark pathologic feature of the pathogenesis of AD. (7) How T-lymphocytes control the inflammation in atopic dermatitis is not understood but will be central to finding the optimal treatment for the disease.

Triggers

Both allergic and nonallergic triggers can result in flares of atopic dermatitis. Substances that dehydrate the skin such as harsh soaps and hard water promote xerosis. Other triggers include rapid temperature changes, low humidity, and emotional stress. The dry skin typical of AD favors colonization of Staphylococcus aureus. This bacterium expresses superantigens that promote lymphocyte activation independent of allergens and may be important in flares of AD. (9) Household dust mites and animal dander are common aeroallergens known to cause AD exacerbations. The household dust mite, Dermatophagoides pteronyssinus, has been shown to precipitate symptoms of atopic dermatitis and other atopic diseases such as asthma and allergic rhinitis. (12) Pollutants and smoke have also been suggested to be important triggers.

Most patients with atopic dermatitis easily identify any foods that cause flares of their dermatitis, as symptoms occur soon after ingestion of these foods and are reproducible with repeated ingestion over time. (13) Common foods that cause food allergies include eggs, milk, wheat, soy, peanuts, and fish. All of these foods have been associated with flares of atopic dermatitis in patients who demonstrate food-specific IgE. Many clinical studies have been able to demonstrate the relation between food allergies and atopic dermatitis. In double-blind, placebo-controlled oral food challenges, food allergens were shown to cause an increase in symptoms such as pruritus and skin eruptions in patients with AD and food allergies. When the causal food allergens were removed, the symptoms resolved but could be elicited again if these foods were reintroduced into the diet. (13)

Diagnostic Testing

Patients with atopic dermatitis produce IgE to a wide variety of inhalant, environmental, and food allergens. However, the presence of IgE to specific allergens does not necessarily correlate with atopic symptoms on exposure to them. For instance, the presence of a household dust mite (D. pteronyssinus)-specific serum IgE test in atopic patients does not correlate with the severity of symptoms related to D. pteronyssinus hypersensitivity. In fact, patients demonstrating D. pteronyssinus-specific IgE in their serum may not exhibit any flares of atopic dermatitis when exposed to the household dust mite. (14) For this reason, avoidance measures for AD patients with D. pteronyssinus-specific IgE are not always effective. One study showed an improvement in atopic dermatitis with reduced exposure to the household dust mite antigen in individuals with household dust mite-specific IgE, whereas another did not. (14), (15)

Thus, allergen-specific IgE levels in the absence of a history of symptoms on exposure are not useful in either avoidance or treatment. Therefore, allergy skin testing and in vitro testing for IgE by the radioallergosorbent test are used to confirm the clinical suspicion of allergic triggers obtained by history, not for diagnosis.

In the atopy patch test, presently used for research purposes only, allergens known to elicit IgE-mediated hypersensitivity reactions are used for epicutaneous patch testing to identify atopic triggers. Patch testing is applied to the back for 48 to 72 hours, with daily examination of the area. (16) Positive results may occur as early as 24 hours or as late as 96 hours. Some studies suggest that atopy patch test results correlate with atopic history, symptoms, skin prick testing, and IgE levels. One study compared the three methods of diagnostic testing using aeroallergens. Atopy patch testing had a higher degree of specificity but less sensitivity than skin prick testing and radioallergosorbent test in detection of allergens triggering atopic dermatitis. (17)

Treatment

The major approach to the management of atopic dermatitis is avoidance of triggers (Table 2). If the offending allergens can be identified on the basis of the history and diagnostic testing, avoidance is a key to fewer flares.

Patients with food-associated exacerbations of AD should eliminate those foods from their diet. Dietary modification seems not only important for those with specific food triggers but may also be worthwhile during pregnancy and lactation. Studies of mothers pregnant with children at high risk for development of AD have shown that mothers who eliminated the more typical allergenic foods (milk, eggs, and fish) from their diet during pregnancy and breast-feeding periods had infants with less AD and food allergy during infancy. When these children were followed, the incidence of AD but not food allergy was decreased when they were placed on table foods. (13)

Unfortunately, avoidance of known triggers alone often is not sufficient to prevent AD exacerbations. (4) Emollients are the treatment mainstays of atopic dermatitis, as xerotic skin is highly pruritic. Lotions have more water and less oil and may lead to dehydration because of evaporation of the water. Creams (only small water content) or ointments (no water content) are better choices for hydrating the skin. Emollients such as Eucerin (Beiersdorf UK, Buckinghamshire, UK), Aquaphor (Beiersdorf), or petroleum jelly are best when applied after bathing to trap the water next to the skin and provide better hydration to decrease xerosis. Skin hydration is best maintained with fewer showers or baths, use of tepid water, and patting dry instead of rubbing after bathing. Mild unscented soaps such as Dove (Johnson & Johnson, New Brunswick, NJ) and Aveeno (Johnson & Johnson) are recommended.

Most AD patients are colonized with Staphylococcus aureus. Because of this, superinfection of dermal lesions and occasionally systemic bacterial infections occur. Treatment of infections with appropriate antibiotics including topical mupirocin (Bactroban; SmithKline Beecham Pharmaceuticals, Morristown, NJ) is central to the treatment of atopic dermatitis.

[FIGURE 2 OMITTED]

For active symptoms and exacerbations, antipruritic and anti-inflammatory medications must be used. Despite the best efforts to keep the skin moisturized and avoid xerosis, many AD patients suffer from pruritus of skin lesions. The use of antipruritic medications including nonsedative and sedative antihistamines (eg, cetirizine, diphenhydramine, hydroxyzine) is useful.

Topical cortices are used for active inflammation of dermal lesions. The lowest effective potency of topical cortices is desired for local treatment of lesions (Table 3). Mixing the emollient and the cortices is an effective method of treatment (e.g., the medium-potency steroid triamcinolone mixed with the emollient Eucerin or Aquaphor in a 1:1 ratio and applied to affected areas). The patient should be counseled on the skin atrophy that can occur when topical cortices are used over a prolonged time. It is also important to remember that the groin, axilla, and face absorb these medications more readily and can thin skin quicker than other areas of the body. Therefore, a low-potency corticosteroid such as 1.0% hydrocortisone ointment is the most desirable for these regions. Risks from topical steroids include fungal infections, impetigo, viral warts, and herpes simplex. (18) Discontinuation of topical cortices may lead to a flare of symptoms. Oral cortices should be avoided if possible and reserved for severe disease over short periods during extreme flares. When used, oral steroids require a long, slow taper to prevent rebound flare after its use.

Topical tacrolimus (Protopic; Fugisawa Healthcare, Japan) and pimecrolimus (Elidel; Novartis Pharmaceuticals Corporation, Basel, Switzerland) have been medical break-throughs for those that have had atopic dermatitis for years. This new nonsteroidal class of immune response modulators works by inhibiting T-cell activation and cytokine release. These drugs downregulate Fc[euro]RI expression on Langerhans cells, which in turn decreases IgE production in dermal lesions. (18) Three 12-week, double-blind, randomized studies in three separate clinics and two open-labeled, single-arm, multicenter, long-term studies involving 1,554 patients were performed to assess the risk for drug-related cutaneous infections with tacrolimus treatment. The risk for infection was no greater with topical tacrolimus than with the vehicle alone. (18) In another study comparing tacrolimus and 1% hydrocortisone acetate, tacrolimus, in both strengths (0.25 and 0.1%), was more effective than 1% hydrocortisone acetate for the treatment of moderate to severe atopic dermatitis. No adverse side effects were observed except mild burning, which resolved with continued use. When treatment with tacrolimus was discontinued, dermatitis did not flare. (19)

Montelukast (Singulair; Merck & Co., Whitehouse, NJ) is a leukotriene antagonist that is currently approved by the U.S. Food and Drug Administration for asthma. The Hanifin-Rajka criteria were used in a treatment trial with montelukast to rate the level of induration, erythema, excoriation, lichenification (Fig. 2), scaling, and erosion on eight patients with mild to moderate atopic dermatitis. Although there was some improvement, it appears this drug may be more useful as adjunctive rather than primary treatment for atopic dermatitis. (20) The role of allergic immunotherapy as treatment for AD has not thus far been proved to be effective; however, this mode of therapy requires further exploration. A recommended treatment algorithm for atopic dermatitis requires measures to be taken for maintenance therapy and for acute flares (Fig. 3).

[FIGURE 3 OMITTED]

Although much is known about the cause, pathogenesis, risk factors, testing, and treatment for atopic dermatitis, more research is warranted to fully appreciate and understand the disease. New treatment options for atopic dermatitis are emerging as we better understand the immunopathology of this immunologic disease.

Key Points

* Atopic dermatitis is an immunologic disease.

* The immunopathogenesis reflects the T-helper 2 type of hypersensitivity response.

* A new class of medications, represented by tacrolimus, effectively treats this condition.

From the Departments of Pediatrics and Medicine, University of Mississippi Medical Center, Jackson, MS.

Reprint requests to Angela Ahuja, MD, Department of Pediatrics, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216. Email: [e-mail]

Accepted August 19, 2003.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9611-1068

References

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2. Correale CE, Walker C, Murphy L, et al. Atopic dermatitis: A review of diagnosis and treatment. Am Fam Physician 1999;60:1191-1198, 1209-1210.

3. Fitzpatrick TB, Johnson RA, Wolff K, et al. Atopic dermatitis, in Color Atlas and Synopsis of Clinical Dermatology: Common & Serious Diseases. New York, McGraw-Hill, 2001, ed 4, pp 30-35.

4. Shaw JC. Atopic dermatitis. UpToDate 2002;10:1-10. Available at: http://www.uptodate.com/physicians/rheumatology_toclist.asp#Allergy. Accessed September 17, 2003.

5. Williams HC. Epidemiology of atopic dermatitis. Clin Exp Dermatol 2000;25:522-529.

6. Larsen FS, Hanifin JM. Epidemiology of atopic dermatitis. Immunol Allergy Clin North Am 2002;22:1-25.

7. Akdis M, Trautmann A, Klunker S, et al. T cells and effector functions in atopic dermatitis. ACI Int 2002;14:61-64.

8. Fujisawa T, Fujisawa R, Kato Y, et al. Presence of high contents of thymus and activation-regulated chemokine in platelets and elevated plasma levels of thymus and activation-regulated chemokine and macrophage-derived chemokine in patients with atopic dermatitis. J Allergy Clin Immunol 2002;110:139-146.

9. Wollenberg A, Kraft S, Oppel T, et al. Atopic dermatitis: Pathogenetic mechanisms. Clin Exp Dermatol 2000;25:530-534.

10. Reich K, Hugo S, Middel P, et al. Evidence for a role of Langerhans cell-derived IL-16 in atopic dermatitis. J Allergy Clin Immunol 2002;109:681-687.

11. Iwasaki M, Nagata K, Takano S, et al. Association of a new-type prostaglandin D2 receptor CRTH2 with circulating T helper 2 cells in patients with atopic dermatitis. J Invest Dermatol 2002;119:609-616.

12. Mascia F, Mariani V, Giannetti A, et al. House dust mite allergen exerts no direct proinflammatory effects on human keratinocytes. J Allergy Clin Immunol 2002;109:532-538.

13. Sicherer SH, Sampson HA. Atopic dermatitis: An update for the next millennium. J Allergy Clin Immunol 1999;104.

14. Shah D, Hales J, Cooper D, et al. Recognition of pathogenically relevant house dust mite hypersensitivity in adults with atopic dermatitis: A new approach? J Allergy Clin Immunol 2002;109:1012-1018.

15. Thestrup-Pedersen K. Environmental factors and atopic dermatitis: How could they influence disease expression? ACI Int 2002;14:165-169.

16. Slavin R. Contact dermatitis, in Patterson R, Grammer LC, Greenberger PA (eds): Allergic Diseases: Diagnosis and Management. Philadelphia, Lippincott-Raven 1997, ed 5, pp 413-424.

17. Darsow U, Ring J. Atopic eczema, allergy, and atopy patch test. ACI Int 2002;14:170-173.

18. Fleischer AB Jr, Ling M, Eichenfield L, et al. Tacrolimus ointment for the treatment of atopic dermatitis is not associated with an increase in cutaneous infections. J Am Acad Dermatol 2002;47:562-570.

19. Reitamo S, Van Leent EJ, Ho V, et al; European/Canadian Tacrolimus Ointment Study Group. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunol 2002;109:539-546.

20. Yanase DJ, David-Bajar K. The leukotriene antagonist montelukast as a therapeutic agent for atopic dermatitis. J Am Acad Dermatol 2001;44:89-93.

RELATED ARTICLE: Table 1. The U.K. refinement of the Hanifin-Rajka diagnostic criteria for atopic dermatitis in children for use in epidemiologic studies (a)

A case of atopic dermatitis in accordance with the U.K. diagnostic criteria must include:

An itchy skin condition in the past 12 mo plus three or more of:

1. Onset below the age of 2 yr (b)

2. History of flexural involvement

3. History of generally dry skin

4. Personal history of other atopic disease (c)

5. Visible flexural dermatitis as per photographic protocol

(a) Adapted from, Williams HC. Epidemiology of atopic dermatitis. Clin Exp. Dermatol 2000;25:522-529.

(b) Not used in children under 4 yr of age.

(c) In children under 4 yr, history of atopic disease in a first-degree relative may be included.

RELATED ARTICLE: Table 2. Approach to treatment of symptoms of atopic dermatitis

Triggers

Identify and avoid

Xerosis

Decrease number of baths, take showers using tepid water, pat dry and avoid rubbing

Use mild soaps (Dove unscented) and mild detergents (Dreft)

Use emollients on a regular basis (Eucerin cream, Aquaphor cream, petroleum jelly)

Pruritus

Antihistamines (examples)

Cetirizine (Zyrtec) 10 mg every day

Hydroxizine (Atarax) 10-50 mg every day or twice daily

Sinequan (Doxepin) 10-50 mg every bedtime

Diphenhydramine (Benadryl) 20-50 mg every 6 hr

Infection

Good hygiene, trim nails

Antibiotics (antistaphylococcal)

Topical: mupirocin

Oral: cephalexin

Inflammation

Topical corticosteroids

Low-potency (hydrocortisone 0.1%)

Medium-potency (triamcinolone 0.2%)

High-/super-high-potency (betamethasone 0.05%)

Nonsteroidals

Tacrolimus (Protopic)

Pimecrolimus (Elidel)

Montelukast (Singulair) 4-10 mg every day

RELATED ARTICLE: Table 3. List of common topical cortices used, categorized by potency

Low-potency

Hydrocortisone acetate 0.5, 1, and 2.5%

Triamcinolone acetonide 0.025%

Alclometasone dipropionate 0.05%

Intermediate-potency

Desonide 0.05%

Mometasone furoate 0.1%

Hydrocortisone valerate 0.2%

Triamcinolone acetonide 0.1, 0.2%

High-potency

Betamethasone dipropionate 0.05% (cream, lotion)

Triamcinolone acetonide 0.5%

Fluocinonide 0.05%

Super-high-potency

Betamethasone dipropionate 0.05% (ointment, gel)

Diflorasone diacetate 0.05%

Clobetasol propionate 0.05%

Angela Ahuja, MD, Kelly Land, CFNP, and Cheryl J. Barnes, MD