managing childhood atopic dermatitis

AdvancesIn Therapy®

Volume 20 No. 3May/June 2003

Managing ChildhoodAtopic Dermatitis

Alexander K. C. Leung, MBBS, FRCPDepartment of PediatricsUniversity of Calgary

Kirk A. Barber, MD, FRCPCDepartments of Internal Medicine and Community Health SciencesUniversity of CalgaryCalgary, Alberta, Canada

ABSTRACT

Atopic dermatitis, a chronic inflammatory skin disorder that affects up to20% of school-aged children, can profoundly influence quality of life.Basic therapy consists of avoidance of triggering factors and optimal skincare. Until now, corticosteroids have been the usual treatment for acuteflares. Short-term safety profiles are reasonable, but long-term use of cor-ticosteroids may involve significant adverse effects. Topical immunomod-ulators (tacrolimus and pimecrolimus) are beneficial and safe for adultsand children and represent a major new alternative to chronic cortico-steroid use, especially in children.

Keywords: atopic dermatitis; children; immunomodulator;tacrolimus; pimecrolimus

INTRODUCTION

Atopic dermatitis is a chronically relapsing dermatosis character-ized by pruritus, erythema, vesiculation, papulation, exudation, exco-riation, crusting, scaling, and sometimes lichenification.1 Lay peopleoften call the condition eczema (Greek ekzema, “to erupt” or “boilout”). Prevalence has increased in recent years, and atopic dermatitisnow affects approximately 7% to 20% of school-aged children.2Because of associated emotional stress and sleep disruption, theimpact on the quality of life of patients and families can be signifi-cant.3,4 Although there is no cure, control is possible in most patientswith pharmacotherapy and adherence to preventive measures.

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PATHOGENESIS AND ETIOLOGY

Atopic dermatitis involves defective cell-mediated immunity related, in part, toan imbalance in two subsets of CD4 T-cells5 that creates a predominance of T-mem-ory cells in the T-helper 2 pathway. T-helper 2 cells express a set of cytokines (inter-leukins-4, -5, -10, and -13) that contribute to the hypereosinophilia, high serum IgElevels, sustained cutaneous inflammation, histamine release, and pruritus charac-teristic of the disorder.5

A strong genetic predisposition is evidenced by the familial nature of the diseaseand the high concordance in monozygotic twins.6 Environmental factors, such ascontact irritants, allergens, sweating, microbes, and stress, trigger or exacerbateatopic dermatitis in susceptible individuals.7

DIAGNOSIS AND CLINICAL FEATURES

There is no laboratory gold standard for the diagnosis of atopic dermatitis.According to criteria articulated by the United Kingdom Working Party in 1994,8

atopic dermatitis is present if a pruritic skin condition is accompanied by three ormore of the following: history of flexural dermatitis (or dermatitis on the cheeks inchildren younger than 10 years of age); personal history of asthma or hay fever (oratopic history in a first-degree relative in children younger than 4 years of age); gen-eralized xerosis in the past year; visible flexural eczema (or eczema on thecheeks/forehead and on the extensor extremities in children younger than 4 yearsof age); and onset before age 2 years (for children older than 4 years).

Approximately 60% of children with atopic dermatitis manifest the disease by thefirst year of life and an additional 30% before the age of 5 years.9,10 In infants,involvement of the face and scalp is common, although the extensor surfaces of theextremities and the trunk may also be affected.11 In older children and adolescents,the neck and antecubital and popliteal fossae usually display the eruption.11

Lesions are classified as acute, subacute, or chronic.12 Acute lesions are intenselypruritic, erythematous papules, papulovesicles, or weeping skin.12 Subacute lesionsare erythematous scaling papules or plaques; chronic lesions are characterized byprominent scaling and lichenification in classically affected body areas.

Complications

Bacterial infection, most commonly with Staphylococcus aureus, is the main com-plication of atopic dermatitis,1 which also increases the risk for widespread herpessimplex infection (Kaposi varicelliform eruption), verruca vulgaris (warts), mollus-cum contagiosum, and superficial fungal infections.11,13

Ocular complications of longstanding atopic dermatitis include eyelid dermatitis,chronic blepharitis, keratoconjunctivitis, vernal conjunctivitis, keratoconus, uveitis,and cataracts.13 It is unclear whether cataract is due to atopic dermatitis per se orresults from the extensive use of corticosteroids.13

Children with atopic dermatitis may suffer from lack of sleep, constant itching,emotional stress, lowered self-esteem, and psychological disturbance.14 The disrup-tion of school, family, and social interactions can severely impair quality of life andextends beyond the child.4,14

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Childhood Atopic Dermatitis

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MANAGEMENT

Successful treatment requires a systemic multipronged approach that consists ofavoidance of triggering factors, optimal skin care, and pharmacotherapy duringacute excerbations.

Avoidance of Triggering Factors

Irritants, allergens, and emotional stress may lead to skin flares in children withatopic dermatitis. Soaps, detergents, washing powders, fabric softeners, and per-fumed products should be avoided as much as possible. Soaps should have minimaldefatting activity and a neutral pH. Nonsoap agents are least irritating and preferred.11

Also to be avoided are woolen or abrasive clothing15—children do best wearingcotton clothing—and extremes of temperature.

Control of house-dust mites may improve atopic dermatitis in patients with thisallergy.16 Among recommended measures are use of allergen-impermeable coversfor pillows and mattresses, washing of bedding in hot water, removal or frequentvacuuming of carpets and upholstered furniture, and elimination of plants and petsfrom the house.13

Food allergy plays an immunopathogenic role in 30% to 50% of children withatopic dermatitis.17-19 Most children with food allergy react to only one or two of the most common allergens—eggs, cow’s milk, nuts, peanuts, soy, and wheat.19-22 In a study of 350 patients with severe atopic dermatitis,18 food allergy was identified bydouble-blind placebo-controlled food challenges. Within minutes to 2 hours, cuta-neous reactions occurred in 75% of the patients with positive results from challenge,but only 30% of the positive responses consisted solely of isolated cutaneous symp-toms. Most skin manifestations took the form of a markedly pruritic, erythematousrash in sites with a predilection for atopic dermatitis. In a well-designed prospectivestudy of 113 patients with atopic dermatitis,23 marked improvement was noted inthose who were maintained on an allergen elimination diet, compared with a simi-lar group of patients who did not have food allergy or who did not adhere to thediet. For children whose food allergy has been identified, elimination of the offend-ing allergen from the diet seems prudent.

In some high-risk infants, exclusive breastfeeding with introduction of solid foodspostponed until the age of 6 months may delay or prevent the onset of atopic der-matitis.19,24 When breastfeeding is not possible, a partially or completely hydrolyzedhypoallergenic formula is desirable.25,26

Emotional stress often exacerbates the skin lesions of atopic dermatitis. If avoid-ance is not possible, coping mechanisms should be tried.

Optimal Skin CareHydration to maintain the skin’s barrier function is of paramount importance and

can be achieved by daily baths in warm (not hot) water for approximately 5 to 10 min-utes,27 followed by patting the body dry with a towel. A moisturizer should be appliedwithin 3 minutes to prevent evaporation and keep the skin soft and flexible.22

Ointments are most effective but messy; creams are often better tolerated.27 Least help-ful, lotions contain water, alcohol, preservatives, and fragrance. Frequent application

131Advances In Therapy®

Volume 20 No. 3, May/June 2003


of moisturizers throughout the day helps to maintain a high level of hydration in the stratum corneum. Emollient adjunctive therapy has a steroid-sparing effect.28

To avoid injury to the skin from scratching, fingernails should be kept short,smooth, and clean. Light cotton mittens are occasionally necessary to controlscratching at night.

Antihistamines

Although pruritus in atopic dermatitis does not appear to be mediated by hista-mine release, oral antihistamines can provide symptomatic relief at bedtime becauseof their sedative properties11 and may be effective for intense pruritus refractory tomoisturizers and conservative measures. Of the H1 antihistamines, hydroxyzine ismore effective than diphenhydramine and cyproheptadine.29,30 The second-genera-tion antihistamines, such as terfenadine, loratadine, and astemizole, have few cen-tral nervous system effects and are nonsedating; they are also less efficacious in thetreatment of pruritus.30 Topical antihistamines should be avoided because of poten-tial local allergic reactions.

Antibiotics

Antibiotics are indicated for secondary bacterial infections that may exacerbateand complicate an acute flare. Cloxacillin, clindamycin, first-generation cephalo-sporins, or macrolides are most effective against S. aureus.11,27 Topical antibiotics,such as mupirocin and fucidic acid, are often useful on localized areas of impetigi-nous eczema.

Coal Tar Preparations

The anti-inflammatory and antipruritic effects of coal tar preparations may helpto reduce the amount of topical corticosteroid required in long-term maintenancetherapy.11,13 Their tendency to cause stinging and irritation precludes their use foracute disease.21 Disadvantages of tars are odor, dark staining color, and side effectssuch as folliculitis, photosensitization, and contact dermatitis.11

Phototherapy

Ultraviolet radiation may have some benefit in the treatment of refractory atopicdermatitis,27 but usefulness is limited by the availability of lighting systems, cost,and inconvenience,7 as well as by acute phototoxicity and potentially increased riskof skin cancers with prolonged treatment.9,11,31

Corticosteroids

Topical corticosteroids are the mainstay of therapy for atopic dermatitis,11,24 with thechoice of potency depending on the severity, site, and extent of the outbreak. In gen-eral, the least potent corticosteroid that can control the symptom should be used,1,9

and only low-potency agents should be applied to the facial skin, genitalia, and inter-triginous areas.32 Topical corticosteroids should not be applied more than twice a day;frequent use does not improve efficacy and increases the risk of side effects.11




The risk of side effects depends on the potency of the corticosteroid, concomitantuse of occlusion, the area being covered, skin integrity, and duration of treatment.9Compared with adults, children are at higher risk of both local and systemic effects.Local adverse effects include skin atrophy, striae, depigmentation, telangiectasia,decreased subcutaneous adipose tissue, rosacea, perioral dermatitis, folliculitis, andsteroid acne.9,21,27 Among systemic side effects are Cushing’s syndrome, adrenal sup-pression, cataracts, glaucoma, and growth retardation.27,33,34 Topical corticosteroidsshould be used with caution near the eyes to minimize the risk of cataracts and glau-coma.9,35 Tachyphylaxis may occur with prolonged treatment. In children, systemiccorticosteroids should be reserved for recalcitrant cases and used for the shortesttime possible while awaiting response to other therapies.1

Systemic Immunosuppressants

Cyclosporine blocks T-cell activation and suppresses cytokine secretion.9

Cyclosporine is beneficial for severe atopic dermatitis unresponsive to topical corti-costeroids, but the dermatitis will return after treatment ceases, although not alwaysas severely.5 Nausea, hypertension, and hepatic and renal toxic reactions limit use-fulness.5,9 Cyclosporine is not effective when applied locally.

Topical Immunomodulators

The newly introduced tacrolimus ointment and pimecrolimus cream work bybinding to a cytoplasmic immunophilin.9,35 The complex inhibits the activity of cal-cineurin to dephosphorylate the transcription factor required to activate interleukin-2gene transcription, thereby suppressing cytokine production by T-cells.9,31,36 Bothmedications have favorable efficacy and safety profiles.

Tacrolimus, a macrolide lactone produced by Streptomyces tsukubaensis, has 10 to 100 times the potency of cyclosporine.36,37 The ointment is the first topical immuno-modulator formulated for use in children older than 2 years of age31,36 and was safeand effective as short- and long-term therapy in clinical studies.38-43 In a 12-week ran-domized, vehicle-controlled, double-blind, multicenter study of 351 children, 2 to 15 years of age, with moderate to severe atopic dermatitis,41 tacrolimus ointment(0.03% and 0.1% concentrations) was safe and significantly more efficacious than thevehicle. No difference in adverse reactions was noted between the vehicle and thetreatment groups.

A multicenter, randomized, double-blind, parallel-group study compared 0.03%and 0.1% tacrolimus ointment with 0.1% hydrocortisone butyrate ointment, a mid-potent to potent topical hydrocortisone, in 570 adults with moderate to severe atopicdermatitis.44 In this 3-week study, tacrolimus 0.1% had efficacy similar to that ofhydrocortisone. Substantial clinical improvement also occurred with tacrolimus0.03%, albeit less than that with tacrolimus 0.1% and hydrocortisone. A similar mul-ticenter, randomized, double-blind, parallel-group comparison of tacrolimus oint-ment 0.03% and 0.1% with hydrocortisone acetate ointment 1% involved 560children 2 to 15 years of age.45 Both concentrations of tacrolimus were significantlymore effective than hydrocortisone acetate. Tacrolimus 0.1% produced greater clini-cal improvement than 0.03%. No safety concerns were identified.




In the treatment of atopic dermatitis, tacrolimus ointment significantly improvesthe quality of life of children and adults alike.3 Effectiveness does not decrease withtime, and the rebound effect sometimes seen after withdrawal of a topical cortico-steroid does not occur.40 Systemic absorption following topical application is mini-mal.46 Tacrolimus ointment does not decrease collagen synthesis or cause skinabnormalities or depigmentation46,47 and can be used safely over the entire body,including the face and intertriginous areas.35 The most common adverse reactions—transient burning, stinging, itching, and erythema at the application site40,41,43,46—areusually mild or moderate. Their decreased prevalence after the first few days oftreatment probably reflects skin healing.45 In long-term open studies, the risk of skinor nonskin infections was consistent with that expected in atopic dermatitis and didnot increase with cumulative dose.40,48,49 Safety studies of up to 3 years have notrevealed any new adverse events.50

Pimecrolimus, a derivative of the macrolactam ascomycin, reduces symptoms ofatopic dermatitis in adult and pediatric patients when applied topically.2,51-53 Twoidentically designed, multicenter, randomized, controlled trials compared pime-crolimus cream 1% with vehicle in 403 children 2 to 17 years of age.2 The random-ization was 2:1, and both groups received treatment twice daily for 6 weeks. Pooledresults showed significant alleviation of symptoms and signs with pimecrolimus com-pared with vehicle. Another study54 randomly assigned 713 patients, 2 to 17 years ofage, with mild to moderate atopic dermatitis treated with emollients to pimecrolimusor vehicle for 1 year. Twice-daily application commenced at the early appearance ofsymptoms or signs and continued until clearance. Both groups used a midpotent cor-ticosteroid for disease flares not controlled by either emollients and pimecrolimus oremollients and vehicle. Fewer pimecrolimus-treated patients required topical corti-costeroid therapy compared with controls, and the pimecrolimus group spent fewerdays using a topical corticosteroid. Significantly lower median scores on the EczemaArea and Severity Index indicated better disease control with pimecrolimus.54

Pimecrolimus improves the quality of life in family members of treated children.14

Absorption through the skin is negligible, even in children with extensive lesions.55

Side effects are similar to those of tacrolimus.53,56

CONCLUSIONS

Atopic dermatitis follows a highly variable course with exacerbations and remis-sions. Although there is no cure, avoidance of triggering factors, optimal skin care, andpharmacotherapy can produce control in most patients. The majority of cases resolveby adulthood, although 20% to 40% of atopic children remain atopic as adults.7

Topical corticosteroids are currently the most common treatment. Their potencyvaries, and greater efficacy is generally associated with an increased risk of adverseeffects, including cutaneous atrophy, immunosuppression, and tachyphylaxis overtime. Topical immunomodulators are relatively free of side effects and can be safelyused over the entire body, including vulnerable areas of thin skin and periorbitallywithout causing cataracts and glaucoma. Decreased immune surveillance of treatedskin and an increased risk of skin cancer are theoretically possible, but clinical datacollected over 4 years indicate no sign of the latter.57 Topical immunomodulators arecontraindicated during pregnancy and breastfeeding53,58 and are undergoing long-term safety studies.




ACKNOWLEDGMENT

The authors thank Ms. Enrica Ng and Ms. Eudora Cheung for expert secretarialassistance and Mr. Sulakhan Chopra of the University of Calgary medical library forhelp in manuscript preparation. Publication of this manuscript was supported by aneducational grant from Fujisawa Canada Inc. Dr. Barber has received grant/researchsupport from Fujisawa Canada Inc. and Novartis Pharmaceuticals Canada Inc.

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managing childhood atopic dermatitis

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