atopic dermatitis -...

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Th1 responses antagonise development of Th2 cells, adecreased number of infections or the absence of Th1polarising signals (such as endotoxin) during earlychildhood could predispose children to enhanced Th2allergic responses.

Clinical diagnosisAtopic dermatitis offers a wide clinical spectrum rangingfrom minor forms such as pityriasis alba (dry depigmentedpatches) or hand eczema to major forms witherythrodermic rash. The most common forms include theclinical features listed in panel 1.9 Of the major features,pruritus and chronic or relapsing eczematous lesions withtypical shape and distribution are essential for diagnosis.Although pruritus can occur throughout the day, it isusually worse in the early evening and night. Pruritisresults in scratching, lichenification, and prurigo papules.Patients with atopic dermatitis have a reduced thresholdfor pruritus. Allergens, reduced humidity, excessivesweating, and low concentrations of irritants canexacerbate pruritus and scratching.

Acute and subacute skin lesions (figure 1) are oftenseen in children and are characterised by intensely pruriticerythematous papules associated with excoriation andserous exudate. Chronic atopic dermatitis is characterisedby lichenification, papules, and excoriations. At all stagesof this disease, patients usually have dry lacklustre skin.The distribution and skin reaction pattern variesaccording to the patient’s age and disease activity. Duringinfancy, atopic dermatitis is generally more acute andmainly affects the face, scalp, and extensor surfaces of theextremities. In older children and in those who have long-standing skin disease, the patient develops lichenificationand localisation of the rash to the flexural folds of theextremities. Chronic hand eczema can be the primarymanifestation of many adults with atopic dermatitis.Panel 2 lists other disorders that share symptoms andsigns with atopic dermatitis. These should be consideredand ruled out before a diagnosis of atopic dermatitis ismade.

Atopic dermatitis is a highly pruritic chronic inflammatoryskin disease that commonly presents during early infancyand childhood but can persist or start in adulthood.1

Interest in this disease has been sparked by reports of itsincreasing prevalence and the significant adverse effects itcan have on quality of life. At least two types of atopicdermatitis have been identified: an extrinsic typeassociated with IgE-mediated sensitisation, which affects70–80% of patients; and an intrinsic type without IgE-mediated sensitisation, which affects 20–30% of patients.2

Here, we will discuss some of the advances in ourunderstanding of this disease and new treatmentapproaches that have been introduced.

EpidemiologyAtopic dermatitis is a major public-health problemworldwide with a lifetime prevalence in children of10–20%, and a prevalence of 1–3% in adults.3 Prevalenceof this disease has increased by two to three-fold during thepast three decades in industrialised countries, but remainsmuch lower in agricultural regions such as China, easternEurope, and rural Africa. Moreover, higher prevalenceshave been recorded in urban regions than in rural regionsof developed countries, and the disease is more common inhigher social class groups.4

Wide variations in prevalence have been identifiedwithin countries inhabited by similar ethnic groups,suggesting that environmental factors determineexpression of atopic dermatitis.5 Results of comparativestudies in former east and west Germany have confirmedthat lifestyle and environment play a major part inexpression of atopic diseases, including atopic dermatitis.6

Some of the risk factors associated with the rise in atopicdisease include small family size, increased income andeducation, migration from rural to urban environments,and increased use of antibiotics—ie, the so-called westernlifestyle.7 These observations are lent support by studies8 inwhich allergic responses were shown to be driven by T-helper type (Th) 2 immune responses, whereasinfections are induced by Th1 immune responses. Since

Atopic dermatitis

Donald Y M Leung, Thomas Bieber

Atopic dermatitis is a highly pruritic chronic inflammatory skin disorder affecting 10–20% of children worldwide.Symptoms can persist or begin in adulthood. It is also the most common cause of occupational skin disease in adults.This disease results from an interaction between susceptibility genes, the host’s environment, pharmacologicalabnormalities, skin barrier defects, and immunological factors. New management approaches have evolved fromadvances in our understanding of the pathobiology of this common skin disorder.

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Lancet 2003; 361: 151–60

Division of Pediatric Allergy and Immunology, National JewishMedical and Research Center, Denver, CO, USA, and Departmentof Pediatrics, University of Colorado Health Sciences Center,Denver, CO (Prof D Y M Leung MD); Department of Dermatology,University of Bonn, Bonn, Germany (Prof T Bieber MD)

Correspondence to: Prof Donald Y M Leung, National Jewish Medicaland Research Center, 1400 Jackson Street, Room K926, Denver,CO 80206, USA(e-mail: [email protected])

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THE LANCET • Vol 361 • January 11, 2003 • www.thelancet.com 151

Search strategy and selection criteria

We did a computer-aided search of PubMed from 1990through May, 2002, for aspects of atopic dermatitis pertinentto this review, to supplement our existing awareness of theprimary published work. We searched using the keywordsatopic dermatitis and eczema. Because of limitations on thenumber of citations, we made selections from the 2043reports published on atopic dermatitis in the past decade tosupport our interpretations with criteria for assessingexperimental studies and evidence-based medicine.


PathophysiologyInteractions between susceptibility genes, the host’senvironment, pharmacological abnormalities, andimmunological factors contribute to the pathogenesis ofatopic dermatitis.10 Most of the progress made inunderstanding the immunology of this disease is related tothe IgE-mediated or extrinsic form of the disease. Clearly,atopic dermatitis has an immunological basis—asconfirmed by the observation that primary T-cellimmunodeficiency disorders frequently have raisedconcentrations of serum IgE and eczematoid skin lesionsthat are cleared after successful bone marrowtransplantation.11 In animals, atopic dermatitis does notoccur in the absence of T cells.12

The systemic immune responseMost patients with atopic dermatitis have peripheralblood eosinophilia and increased serum IgEconcentrations. Nearly 80% of children with atopicdermatitis develop allergic rhinitis or asthma, suggestingthat allergen sensitisation through the skin predisposespeople to respiratory diseases.13 Peripheral bloodmononuclear cells from patients with atopic dermatitishave a decreased capacity to produce interferon �, whichis inversely correlated with serum IgE concentrations.This association could be due to a deficiency ofinterleukin 18, an inducer of interferon � production.14

An increased frequency of allergen-specific T cellsproducing interleukin 4, 5, and 13, but little interferon �,in the peripheral blood of patients with atopic dermatitishas also been recorded.15 These immunological changesare important because interleukins 4 and 13 are the onlycytokines that induce germline transcription at the � exon, thereby promoting isotype switching to IgE.These cytokines also induce expression of vascularadhesion molecules such as VCAM-1, which areinvolved in eosinophil infiltration and downregulateTh1-type cytokine activity. By contrast, interferon �inhibits synthesis of IgE, proliferation of Th2 cells, andexpression of the interleukin 4 receptor on T cells.Interleukin 5 plays a key part in development, activation,and survival of eosinophils. The cytokine micromilieu inwhich T-cell development takes place, pharmacologicalfactors, the costimulatory signals used during T-cellactivation, and the antigen-presenting cell determine theoutcome of the T-cell response.16–18

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152 THE LANCET • Vol 361 • January 11, 2003 • www.thelancet.com

Panel 1: Clinical features of atopic dermatitis*Essential featuresPruritusFacial and extensor eczema in infants and childrenFlexural eczema in adultsChronic or relapsing dermatitis

Frequently associated featuresPersonal or family history of atopic disease XerosisCutaneous infectionsNon-specific dermatitis of the hands or feetRaised serum IgE concentrationsPositive immediate-type allergy skin testsEarly age of onset

Other featuresIchthyosis, palmar hyperlinearity, keratosis pilarisPityriasis albaNipple eczemaWhite dermatographism and delayed blanch responseAnterior subcapsular cataracts, keratoconusDennie-Morgan infraorbital folds, orbital darkeningFacial erythema or pallor

*Other skin disorders that can mimic atopic dermatitis should beexcluded.

Figure 1: Clinical (upper) and histological (lower) findings inacute and chronic atopic dermatitisAcute (left) and chronic (right) lesions in atopic dermatitis. Magnification �100.

Panel 2: Differential diagnosis of atopic dermatitis

Chronic dermatosesSeborrhoeic dermatitisContact dermatitis (allergic or irritant)Nummular eczemaPsoriasisIchthyoses

Congenital disordersNetherton's syndromeFamilial keratosis pilarisInfections and InfestationsScabiesHIV-associated dermatitisDermatophytosis

Malignant diseasesCutaneous T-cell lymphoma (Mycosis, fungoides/Sézarysyndrome)Letterer-Siwe disease

Immunological disordersDermatitis herpetiformisPemphigus foliaceusGraft versus host diseaseDermatomyositis

ImmunodeficienciesWiskott-Aldrich syndromeSevere combined immunodeficiencyHyper-IgE syndromeDiGeorge syndrome

Metabolic disordersZinc deficiencyPyridoxine (vitamin B6) and niacinMultiple carboxylase deficiencyPhenylketonuria


Skin pathology and immunopathologyClinically unaffected skin of patients with atopicdermatitis is not normal, but reveals a sparse perivascularT-cell infiltrate.19,20 Acute eczematous skin lesions arecharacterised by marked epidermal intercellular oedema(spongiosis) (figure 1). Antigen-presenting cells (eg,Langerhans cells, inflammatory dendritic epidermal cells,and macrophages) in lesional and, to a lesser extent inskin without lesions, have IgE molecules (figure 2).21 Indermis with acute lesions, there is a striking infiltration ofCD4 activated T cells. Chronic lichenified lesions arecharacterised by an acanthotic epidermis with elongationof the rete ridges, parakeratosis, and only minimumspongiosis (figure 1). Chronic lichenified lesions have anincreased number of IgE-bearing Langerhans cells andinflammatory dendritic epidermal cells in the epidermis,and macrophages dominate the dermal mononuclear cell infiltrate. These lesions also contain eosinophils,which are thought to contribute to inflammation andtissue injury through production of reactive oxygenintermediates and proinflammatory cytokines and releaseof toxic granule proteins.

Cytokine expression—Two approaches have providedimportant information about the cytokine patternexpressed in acute versus chronic atopic dermatitis(figure 3). First, analyses of biopsy samples fromunaffected skin of patients with atopic dermatitis, ascompared with healthy non-atopic skin, have an increasednumber of Th2 cells expressing mRNA of interleukins 4and 13.22,23 When compared with healthy skin orunaffected skin of patients with atopic dermatitis,

naturally occurring lesional skin has significantly morecells expressing mRNA of interleukins 4, 5, and 13.However, acute atopic dermatitis does not containsignificant numbers of cells expressing mRNA ofinterferon � or interleukin 12. By contrast, chronic atopicdermatitis skin lesions have significantly fewer cellsexpressing mRNA of interleukins 4 and 13, but increasednumbers of cells expressing mRNA of interleukin 5, GM-CSF, interleukin 12, and interferon � than do those ofacute atopic dermatitis.

In another approach using the atopy-patch testtechnique as a model, lesions induced by house dust mites were shown to have two phases: an initial phase with mostly Th2 cells producing interleukin 4 and asubsequent phase after 24–48 h with mainly Th1 cellsproducing interferon �.24 This switch is probably startedby local production of interleukin 12 from infiltratingeosinophils, or inflammatory dendritic epidermal cells, or both.

Activated T cells also induce keratinocyte apoptosis,contributing to the spongiotic process seen in acute atopicdermatitis.25 This process is mediated by interferon �derived from T cells, which upregulates Fas onkeratinocytes. The lethal hit is delivered to keratinocytesby membranous and soluble Fas-ligand produced byepidermotropic T cells.

Antigen-presenting cells—Atopic dermatitis skincontains an increased number of IgE-bearing Langerhanscells and inflammatory dendritic epidermal cellsexpressing the high-affinity receptor for IgE.26 Theseantigen-presenting cells seem to have an important role inallergen presentation to Th2 and Th1 cells, respectively.27

In this regard, high-affinity receptors for IgE contributeto the capture and internalisation of allergens before theirprocessing and antigen presentation to T cells in atopicskin. Langerhans cells positive for these receptors can alsomigrate to the lymph nodes and stimulate naive T cells,thereby contributing to expansion of the pool of Th2 cells.The clinical importance of these cells is supported by theobservation that Langerhans cells with high-affinityreceptors for IgE need to be present to provokeeczematous skin lesions by application of aeroallergens onthe skin of atopic patients.28

Inflammatory cell infiltration—Interleukin 16, achemoattractant for CD4 T cells, is more highly expressedin acute than chronic atopic dermatitis skin lesions.29,30

The C-C chemokines, T cells expressed and secreted(RANTES), monocyte chemotactic protein 4 (MCP4),and eotaxin are also increased in atopic dermatitis skinlesions and probably contribute to the chemotaxis of eosinophils expressing CCR3 and Th2 lymphocytesinto the skin.31,32 Cutaneous T-cell-attracting chemokinescould have a role in the preferential attraction ofcutaneous lymphoid antigen T cells to the skin.33 Selectiverecruitment of Th2 cells expressing CCR4 into skin withatopic dermatitis might also be mediated by thechemokines MDC and TARC, which are increased inatopic dermatitis.34–36 Persistent skin inflammation inchronic lesions could be because of expression ofinterleukin 5 and GM-CSF in the skin, which lengthensurvival of eosinophils, monocyte-macrophages, andLangerhans cells.37

Mechanical trauma also induces release of tumournecrosis factor � and many other proinflammatorycytokines from epidermal keratinocytes.38 Epidermalkeratinocytes from patients with atopic dermatitis produce significantly higher concentrations of RANTESafter stimulation with tumour necrosis factor � andinterferon �.39 In atopic dermatitis, but not non-atopic

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Figure 2: Dendritic cells in atopic dermatitis skin lesionExpression of CD1a (upper) and IgE (lower). Magnification �100.


dermatitis, keratinocytes are also an important source ofthymic stromal lymphopoietin, which activates dendriticcells to prime naive Th cells to produce interleukins 4 and13 and tumour necrosis factor �.40 These observationsmight explain the link between scratching and thetriggering of Th2-mediated skin inflammation in atopicdermatitis.

GeneticsAtopic dermatitis is a genetically complex, familiallytransmitted disease with a strong maternal influence.Parental atopic dermatitis confers a higher risk tooffspring than does parental asthma or allergic rhinitis,suggesting the existence of genes specific to atopicdermatitis. Several chromosomal regions containpathophysiologically relevant candidate genes, especiallyon chromosome 5q31–33 since it contains a clusteredfamily of Th2 cytokine genes—ie, interleukins 3, 4, 5, and13, and GM-CSF.41 Results of a case-control compar-ison42 have suggested a genotypic association between theT allele of the –590C/T polymorphism of the interleukin 4gene promoter region with atopic dermatitis. That thisallele is associated with increased activity of theinterleukin 4 gene promoter suggests that it might affectatopic dermatitis predisposition. Similarly, variants of the interleukin 13 coding region, a gain-of-functionpolymorphism in the � subunit of the interleukin 4receptor (16q12), and a functional mutation in thepromoter region of RANTES (17q11) have a role inexpression of atopic dermatitis. Atopic dermatitis hasbeen controversially linked to markers at chromosome11q13, including the gene encoding for the � chain of thehigh affinity receptor for IgE.43 Atopic dermatitis has alsobeen associated with a low-producer transforming growthfactor �-cytokine genotype,44 which could contribute toincreased skin inflammation.

Genome-wide linkage studies have also been done toidentify susceptibility loci for atopic dermatitis. Lee andcolleagues45 suggested that atopic dermatitis is linked to

chromosome 3q21, a region that encodes the costimu-latory molecules CD80 and CD86. By contrast, Cooksonand coworkers46 reported that both atopic dermatitis andpsoriasis were linked to loci on chromosome 1q21 and17q25, suggesting that common candidate genes areinvolved in control of skin inflammation. Since most ofthese studies included patients with raised concentrationsof IgE—ie, patients with the IgE-mediated (extrinsic)type—the genetic background of the non-allergic(intrinsic) type remains elusive. However, since thesepatients usually have the same family history of atopicdiseases as the classical IgE-mediated form, at least oneset of common genes unrelated to IgE-biology is expected.

Immunological triggersFoodsFood allergens induce skin rashes in nearly 40% ofchildren with moderate to severe atopic dermatitis.47 Foodallergies in patients with atopic dermatitis might inducedermatitis and contribute to severity of skin disease insome patients, whereas in others urticarial reactions, ornon-cutaneous symptoms are elicited. Infants and youngchildren with food allergies generally have positiveimmediate skin tests or serum IgE directed to variousfoods, especially egg, milk, wheat, soy, and peanut.48

Importantly, T cells specifc to food allergens have beencloned from the skin lesions of patients with atopicdermatitis, providing direct evidence that foods cancontribute to skin inflammation.49 In mice with atopicdermatitis, oral sensitisation with foods results ineczematous skin lesions on repeat oral food challenges.50

AeroallergensPruritus and skin lesions can develop after intranasal orbronchial inhalation challenge with aeroallergens insensitised (specific IgE) patients with atopic dermatitis.51

Epicutaneous application of aeroallergens (eg, house dustmites, weeds, animal danders, and moulds) by atopypatch test on unaffected atopic skin elicits eczematoid

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ThO Th1

Th2

Uninvolved Acute

Allergens

Monocytes

CLA+Th2 cells IgE EosinophilsMacrophages

Circulation

ScratchingMicrobial

toxins

Chronic

IL 13IL 4IL 5

IL 12 IFN �

CytokinesChemokines

Figure 3: Immunological pathways in atopic dermatitisIL=interleukin. Modified from reference 10 with permission from Mosby/Elsevier Science, St Louis.


reactions in 30–50% of patients with atopic dermatitis.52

By contrast, atopy patch tests are usually negative inpatients with respiratory allergy and in healthy volunteers.A combination of effective measures for reduction ofhouse dust mites has been associated with significantimprovement in atopic dermatitis.53,54 The degree of IgEsensitisation to aeroallergens is directly associated with theseverity of atopic dermatitis.55 The isolation from skinlesions with atopic dermatitis and allergen patch test sitesof T cells that selectively respond to Dermatophagoidespteronyssinus and other aeroallergens provides furtherevidence that the immune response in atopic dermatitisskin can be elicited by aeroallergens.52

AutoallergensIn the 1920s, several investigators56 reported that humanskin dander could trigger immediate hypersensitivityreactions in the skin of patients with severe atopicdermatitis, suggesting that these patients made IgEagainst autoantigens in the skin. Most sera from patientswith severe atopic dermatitis contain IgE antibodiesdirected against human proteins.57 Although theautoallergens characterised to date are mainly intracellularproteins,58 they have been detected in IgE immunecomplexes of atopic dermatitis sera, suggesting thatrelease of these autoallergens from damaged tissues couldtrigger responses mediated by IgE or T cells. This notionis supported by the observation that IgE autoallergentitres decrease with successful treatment of atopicdermatitis with ciclosporin,59 suggesting that although IgEimmune responses are initiated by environmentalallergens, allergic inflammation can be maintained byhuman endogenous antigens, especially in severe atopicdermatitis.

Staphylococcus aureusIncreased numbers of S aureus are found in over 90% ofatopic dermatitis skin lesions. The importance of thisorganism is lent support by the observation that, inpatients with atopic dermatitis with secondary infection,treatment with a combination of anti-staphylococcalantibiotics and topical glucocorticoids produces superiorclinical effects than does treatment with topicalglucocorticoids alone.60 One strategy by which S aureusexacerbates or maintains skin inflammation in atopicdermatitis is by secreting superantigens, which stimulatemarked activation of T cells and macrophages.61,62 Ananalysis of the peripheral blood skin-homing CLA+ T cells from these patients and T cells in their skin lesionsshows that they have undergone a T-cell receptor V�expansion consistent with superantigenic stimulation.63,64

Most patients with atopic dermatitis make specific IgEantibodies directed against staphylococcal superantigens;these super antigens to IgE correlate with the severity ofdisease.62 Superantigens augment synthesis of allergen-specific IgE and induce glucocorticoid resistance,suggesting that superantigens could increase severity ofatopic dermatitis through several mechanisms.65,66

Fulfilling Koch’s postulates, application of atopicdermatitis superantigens to the skin induces dermatitis.67

Increased binding of S aureus to skin is probably relatedto underlying atopic dermatitis inflammation. Thisobservation is lent support by the finding that treatmentwith topical glucocorticoids or tacrolimus reduces S aureus counts on atopic skin.68,69 Scratching probablyenhances S aureus binding by disturbing the skin barrierand exposing extracellular matrix adhesins for S aureussuch as fibronectin and collagens. In studies70,71 ofS aureus binding to skin lesions undergoing Th1 versus

Th2 inflammatory responses, bacterial binding wassignificantly greater at skin sites with Th2-mediatedinflammation than at those with Th1-mediatedinflammation because of expression of fibronectininduced by interleukin 4. Atopic dermatitis skin is alsodeficient in antimicrobial peptides needed for hostdefense against bacteria, fungi, and viruses.72 Thus, onceS aureus binds to atopic dermatitis skin, inadequate hostdefence allows bacteria to colonise and predisposepatients to infection.

ManagementSuccessful management of atopic dermatitis requires amultipronged approach involving skin care, identificationand elimination of flare factors, and anti-inflammatorytreatment.73 Randomised controlled trials are especiallyimportant in assessing the effects of treating atopicdermatitis because of the substantial placebo effect in thisdisease.

Skin careIn atopic dermatitis, the disturbed function of the skinbarrier is probably the result of reduced ceramideconcentrations and results in dry skin (xerosis) andenhanced transepidermal water loss.74 Irritants such assoaps or detergents, contact with chemicals, smoke,alcohol and astringents found in toiletries, and abrasiveclothing can worsen the xerosis. Soaps with minimumdefatting activity and a neutral pH are preferred. Xerosiscontributes to development of epithelial microfissures andcracks, which allows entry of skin pathogens, irritants, andallergens. Wet dressings can be used on severely affectedor chronic lesions refractory to skin care. Dressings can bean effective barrier against persistent scratching, allowingmore rapid healing of excoriated lesions.

Every attempt should be made to allow patients to be asnormally active as possible. Some sports such asswimming might be better tolerated than other sportsinvolving intense perspiration, and physical contact, butchlorine should be rinsed off immediately after swimmingand the skin lubricated.

Identification and elimination of triggering factorsPotential allergens can be identified by taking a carefulhistory and doing selective allergy tests. Negative skinprick tests or serum tests for allergen-specific IgE have a high predictive value for ruling out suspected allergens.Positive skin or in-vitro allergy tests, especially to foods, often do not correlate with clinical symptoms andshould be confirmed with controlled food challenges,elimination diets, or atopy patch tests. Avoidance offoods implicated in controlled challenges results inclinical improvement.47,75 As a rule, extensive eliminationdiets, which in some cases can be nutritionally deficient,are useless. Most children who are allergic to foodoutgrow their food hypersensitivity in the first few years oflife, making it less relevant as trigger factor when older.Extended avoidance of house dust mites in sensitisedpatients with atopic dermatitis results in improvement oftheir skin disease. Avoidance measures include use ofhouse dust mite-proof encasings on pillows, mattresses,and boxsprings; washing bedding in hot water weekly;removal of bedroom carpeting; and decreasing indoorhumidity levels.53,54

Unlike allergic rhinitis and extrinsic asthma,immunotherapy with aeroallergens has not been proven tobe effective in treatment of atopic dermatitis. Wellcontrolled studies are still needed to determine the role ofimmunotherapy in this disease, and this approach should

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be reserved for individuals who have a clear cutdemonstrable history of aeroallergen induced atopicdermatitis—eg, seasonal exacerbations to pollen.

Topical anti-inflammatory agentsGlucocorticoids—Topical glucocorticoids are frequentlyused to control acute exacerbation of atopic dermatitis.However, once control of atopic dermatitis is achievedwith a daily regimen of topical glucocorticoids, long-termcontrol can be maintained with twice weekly applicationsof topical fluticasone to regions that have healed but areprone to developing eczema.76 Side-effects from topicalglucocorticoids are directly related to the potency rankingof the compound and the length of use, so the clinicianneeds to instruct the patients and to balance the need for amore potent steroid with the potential for side-effects.Therefore, ultra-high-potency glucocorticoids should beused only for very short periods of time and in regions thatare lichenified but not on the face or intertriginous areas.

Tacrolimus—Topically applied FK-506, or tacrolimus, acalcineurin inhibitor that acts by binding with high affinityto the 12 kDa macrophilin, has been successfully used intreatment of atopic dermatitis. Tacrolimus inhibitsactivation of several key cells involved in atopic dermatitis,including T cells, dendritic cells, mast cells, andkeratinocytes.77 Multicentre blinded vehicle-controlledphase-3 trials with 0·03% and 0·1% tacrolimus ointment,have shown tacrolimus to be both effective and safe inadults and children.78–80 Local burning sensation has beenthe only common adverse event and most patients havegreatly reduced pruritus within 3 days of startingtreatment. In adults, but not children, a dose-responseeffect was seen between 0·03% and 0·1% tacrolimus,especially for patients with severe skin disease.

Long-term open-label studies81 with tacrolimusointment applied on up to 100% body surface area havebeen done in adults and children with sustained efficacyand no important side-effects—eg, no increased skininfections. In addition, unlike topical glucocorticoids,tacrolimus ointment is not atrophogenic and has beenused safely for facial and eyelid eczema. Of note, threechildren with Netherton syndrome, who responded totreatment with 0·1% tacrolimus ointment, hadsubstantial percutaneous absorption of the drug, withserum concentrations well above the therapeutic range.82

In retrospect, this observation is not surprising, sincepatients with Netherton syndrome have a skin barrierdysfunction that puts them at risk for increasedpercutaneous absorption of topical drugs. Since patientswith Netherton syndrome are sometimes misdiagnosedas having atopic dermatitis, this diagnosis should beconsidered in any infant or child with extensiveerythroderma resistant to treatment and monitored forblood tacrolimus concentrations as deemed appropriateby the care provider. Increased blood concentrations oftacrolimus have generally not been reported in patientswith moderate to severe atopic dermatitis. Indeed,quantifiable tacrolimus blood concentrations are isolatedand transient occurrences seen only early in treatment.However, the potential risk of systemic absorption mustbe considered in any child with extensive skin diseasebecause of their high ratio of body surface area toweight. In this situation, especially if patients developinfection or changes in liver or kidney function, plasmadrug concentrations should be obtained. 0·03%tacrolimus ointment has been approved for short-termand intermittent long-term use in for children 2–15 years of age with moderate to severe atopicdermatitis; and 0·03% and 0·1% for adults.

Pimecrolimus—Ascomycin compounds such aspimecrolimus, which has the same mechanism of action astacrolimus, have been developed in topical and oral forms.Like tacrolimus, they inhibit production of Th1 and Th2 cytokines, and inhibit mediator release from mastcells and basophils.83 1% pimecrolimus is effective andsafe in adults and children with atopic dermatitis.84,85

Pimecrolimus cream ointment 1% has been approved forshort-term and intermittent long-term use in mild-moderate atopic dermatitis for patients 2 years and older.When used as maintenance therapy, topical pimecrolimusreduces the number of flares caused by atopic dermatitisand reduces requirements for corticosteroid therapy.86

The approval of topical calcineurin inhibitors fortreatment of atopic dermatitis is a great advance in ourmanagement options for this disease. However, we shouldstill develop guidelines for use of topical corticosteroidsversus calcineurin inhibitors. Topical calcineurininhibitors can be advantageous over topical corticos-teroids in some circumstances, including treatment ofpatients who do not respond well to topical steroids,patients with steroid phobia, and treatment of face andneck dermatitis where ineffective, low-potency topicalcorticosteroids are usually used because of fears ofsteroid-induced skin atrophy. The potential use of topicalcalcineurin inhibitors as maintenance therapy is alsointriguing for prevention of atopic dermatitis flares.86

However, although systemic absorption of thesecompounds are low, the drugs need to be carefullymonitored to rule out the possibility that skin cancers andincreased viral skin infections will appear when suchagents are used long-term.

Tar preparations—Coal tar preparations have anti-pruritic and anti-inflammatory effects on the skin but areless active than glucocorticoids. Their use is restricted tochronic lesions and they can induce folliculitis and photo-sensitivity. There is a theoretical risk of tar being acarcinogen based on observational studies of workersusing tar components in their occupations.

Anti-infectious management Antistaphylococcal antibiotics can be helpful in treatmentof poorly-controlled patients who are heavily colonised orinfected with S aureus.87 Topical mupirocin or fusidic acidis useful in treatment of localised impetiginised lesions. Inpatients with extensive superinfection with sensitive S aureus strains, a course of systemic antibiotics such aserythromycin and the newer macrolide antibiotics(azithromycin and clarithromycin) is usually beneficial.However, for macrolide-resistant S aureus, a penicillinase-resistant penicillin (dicloxacillin, oxacillin, or cloxacillin)and first-generation cephalosporins might be preferred.

Atopic dermatitis can be complicated by recurrent viralskin infections such as warts and mollusca contagiosawhich can reflect local defects in T-cell function.88 Herpessimplex, resulting in Kaposi’s varicelliform eruption or eczema herpeticum can be a serious infection. Afteran incubation period of 5–12 days, many itchyvesiculopustular lesions erupt in a disseminated pattern;vesicular lesions are umbilicated, tend to crop, and often become haemorrhagic and crusted (figure 4). Thepresence of punched-out erosions, vesicles, or infectedskin lesions that do not respond to oral antibiotics shouldinitiate a search for herpes simplex. Antiviral treatment forcutaneous herpes simplex infections is of crucialimportance in patients with widespread atopic dermatitissince life-threatening dissemination has been reported. Inpatients with atopic dermatitis, smallpox vaccination oreven exposure to vaccinated individuals can cause a severe

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widespread skin rash called eczema vaccinatum similar inappearance to eczema herpeticum.

Patients with atopic dermatitis have increasedprevalence of fungal infections compared with non-atopiccontrols. The role of Malassezia furfur (Pityrosporumorbiculare) in atopic dermatitis has been of particularinterest. M furfur is a lipophilic yeast commonly present inthe seborrheic regions of the skin and in the scalp. IgEantibodies against this organism are frequently found inpatients with atopic dermatitis and most frequently inpatients with head and neck dermatitis.89 The potentialimportance of M furfur and other dermatophyte infectionsis further supported by the reduction of atopic dermatitisskin severity in such patients after treatment withantifungal agents.

PhototherapyNatural sunlight is frequently beneficial to patients withatopic dermatitis. However, if the sunlight occurstogether with high heat or humidity, thereby triggeringsweating and pruritus, it can be deleterious to patients.Broad-band ultraviolet B, broad-band ultraviolet A,narrow-band ultraviolet B (311 nm), ultraviolet A-1(340–400 nm), and combined ultraviolet A and Bphototherapy can be useful adjuncts in treatment ofatopic dermatitis.90,91 Photochemotherapy with psoralenand ultraviolet A (PUVA) should be restricted to patientswith severe, widespread atopic dermatitis, although fewinvestigators have compared this treatment with othermodes of phototherapy. Short-term adverse effects withphototherapy can include erythema, skin pain, pruritus,and pigmentation. Potential long-term adverse effectsinclude premature skin aging and cutaneous malignantdiseases.

Extracorporeal photopheresis consists of the passage ofpsoralen-treated leukocytes through an extracorporealultraviolet A light system. Clinical improvement in skinlesions associated with reduced IgE concentrations have

been reported in a few patients with severe, resistantatopic dermatitis who were given extracorporealphotopheresis and topical glucocorticoids.

Systemic treatmentAntihistamines—Reduction of skin inflammation anddryness with topical glucocorticoids and skin care,respectively, will often symptomatically reduce pruritus.Systemic antihistamines act mainly by blocking the H1receptors on dermal mast cells. Since histamine is onlyone of many mediators that can induce pruritus, somepatients might derive minimum benefit from treatmentwith antihistamines. Results of studies92 of theeffectiveness of newer non-sedating antihistamines incontrol of pruritus have varied greatly, although thesedrugs could be useful in patients with atopic dermatitisand concomitant urticaria.

Since pruritus is usually worse at night than during theday, sedating antihistamines such as hydroxyzine ordiphenhydramine offer an advantage when used atbedtime. Doxepin hydrochloride has both tricyclicantidepressant and H1-histamine and H2-histaminereceptor blocking effects. If nocturnal pruritus remainssevere, short-term use of a sedative to allow adequate restmight be appropriate. Treatment of atopic dermatitiswith topical antihistamines is useless and can inducecutaneous sensitisation.

Systemic glucocorticoids—Use of systemic gluco-corticoids, such as oral prednisone, is rarely indicated,since the clinical improvement is frequently followed by asevere rebound flare at discontinuation. Short courses oforal glucocorticoids are sometimes appropriate for anacute exacerbation while other treatment measures arebeing instituted. In this case, it is important to taper thedose and begin intensified skin care, especially withtopical glucocorticoids and bathing followed byapplication of emollients, to prevent rebound flares.

Interferon gamma—Interferon gamma downregulatesTh2 cell function. Treatment with recombinantinterferon gamma results in clinical improvement.93

Reduction in clinical severity of atopic dermatitiscorrelated with the ability of this drug to decrease bloodeosinophilia. However, influenza-like symptoms arecommonly seen side-effects early in the treatment courseand limit use of this treatment.

Ciclosporin—Ciclosporin is a potent immuno-suppressive drug that acts mostly on T cells bysuppressing cytokine transcription. The drug binds tointracellular cyclophilin and thereby acts in a similar wayto tacrolimus and pimecrolimus. Children and adultswith severe atopic dermatitis refractory to conventionaltreatment, can benefit from short-term ciclosporin, withimproved quality of life.94 However, discontinuation oftreatment generally results in relapse flares. Raised serumcreatinine or more substantial renal impairment andhypertension are specific side-effects of concern.

Antimetabolites—Mycophenolate mofetil is a purinebiosynthesis inhibitor used as an immunosuppressant inorgan transplantation, has been used for treatment ofrefractory inflammatory skin disorders.95 Short-term oralmycophenolate mofetil 2 g daily as monotherapy resultsin clearing of skin lesions in adults with atopic dermatitisresistant to other treatment including topical and oralsteroids and PUVA. The drug is generally well tolerated,with the exception of occasional herpes retinitis. Dose-related bone marrow suppression has also been recorded.Not all patients benefit from treatment. Therefore, thedrug should be discontinued if patients do not respondwithin 4–8 weeks.

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Figure 4: Eczema herpeticumMagnification �4.


Methotrexate is an antimetabolite with potent inhibitoryeffects on inflammatory cytokine synthesis and cellchemotaxis. It has been used for patients with recalcitrantatopic dermatitis, though controlled trials are few.

Azathioprine is a purine analogue with anti-inflammatory and antiproliferative effects, which has been used for severe atopic dermatitis, though nocontrolled trials have been reported. Myelosuppression isan important adverse effect, and thiopurinemethyltransferase concentrations can predict individuals at risk.

Complementary approachesEmotional stressors—Patients with atopic dermatitis oftenrespond to frustration, embarrassment, or other stressfulevents with increased pruritus and scratching, and stresscan induce immunological changes in such patients.96,97

Psychological assessment or counselling should beconsidered in patients who have difficulty with emotionaltriggers or psychological problems contributing todifficulty in managing their disease. Relaxation,behavioural modification, or biofeedback can be helpful inpatients with habitual scratching.

Other treatments—Leucocytes from patients withatopic dermatitis have increased cAMP-PDE enzymeactivity. Monocytes from such patients produce raisedconcentrations of PGE2 and interleukin 10, which bothinhibit production of interferon � by T cells. Topicalapplication of PDE inhibitors has shown clinical benefit inatopic dermatitis.17 Intravenous immunoglobulin reducesskin inflammation in patients with refractory atopicdermatitis.98 Results of several studies have also suggestedthat patients with atopic dermatitis benefit from treatmentwith traditional Chinese herbal therapy.99 The possibilityof hepatic toxic effects, cardiac side-effects, oridiosyncratic reactions, however, is a concern. Thespecific ingredients of the herbs also remain to beelucidated and some preparations have been found to becontaminated with glucocorticoids.100

Future directionsAtopic dermatitis is often the first presentation of anindividual destined to a lifetime of allergy and asthma.Since the skin is a highly sensitising organ that contributesgreatly to the systemic allergic response, highly effectivetreatments need to be developed to reduce skininflammation in this disease. Advances are likely to needbetter definitions for the various clinical phenotypes ofatopic dermatitis, including identification of the genesleading to the disease, a better understanding of theimmunoregulatory abnormalities underlying it, and newparadigms for preventing relapses of this skin disorder.Such advances will probably be tied to development ofpharmacogenetics and targeting of effective treatments tosubsets of patients with atopic dermatitis.

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Laboratory diagnosis

Caroline Mackie Ogilvie

Uses of error

Genetics Centre, Guy’s and St Thomas’ Hospital, London SE1 9RT, UK (C M Ogilvie DPhil)

Scientists working in the area of laboratory diagnosis are ingeneral further removed from the consequences of errorthan clinicians who have direct contact with the patients.But none of us likes to get things wrong, and diagnosticerrors in my own field of genetics, such as failing to identifyan abnormal chromosome on karyotype analysis, tend toplunge one into gloom and self-reproach for several days, ifnot weeks, depending on one’s personality.

In the diagnostic laboratory, the final result of a test maybe prone to error from various sources: inherent errors inthe test, leading to incorrect “output”; errors in theinterpretation of the output (such as the example givenabove); and clerical errors in the transfer of information.Inherent errors in the test are sometimes not appreciated;for instance, there is a considerable literature on theabnormal chromosome constitution of a large proportionof early human embryos in vitro, a conclusion based ondata obtained using a technique called FISH(Fluorescence In Situ Hybridization). However, theinherent error rate using FISH is under-appreciated, and itis possible that many of these so-called abnormalities mayin fact have been due to FISH errors. Our department ispart of a successful Preimplantation Genetic Diagnosis(PGD) centre, in which both FISH-based and PCR-basedtests are used to diagnose genetic abnormality in singlecells from human cleavage-stage embryos. These tests aretechnically very demanding and are prone to output errorssuch as those caused by signal overlap (FISH) or singletube contamination (PCR). The nature of such single cellwork makes error estimations difficult, but we do our best,

and these estimates are discussed with prospectivepatients. Our programme has been running successfully forthree years; however, we were shocked and saddenedrecently to hear that an affected baby had been bornfollowing transfer of an embryo diagnosed as free from aserious genetic condition. The couple had declinedprenatal diagnosis. Thorough evaluation of the test resultsshowed that the interpretation of the output was correct.Therefore the possibilities were that either there had beenan output error in the test, or that there had beenspontaneous natural conception. Statistical analysisrevealed that a single abnormal pregnancy was at this pointwell within our estimated error rate. Detailed analysis ofprotocols revealed areas that could be improved—forinstance, better counselling of couples with respect to theuse of contraception during their PGD cycle. Although thepotential error rate could be reduced further byintroducing extra parameters into the test, we realised thatany additional measurements to increase the sensitivitywould also decrease the specificity, thus increasing thechance of excluding normal embryos from transfer due toerrors in the new measurements. As many womenundergoing PGD have small embryo cohorts, a decrease intest specificity could significantly jeopardise their chancesof establishing a pregnancy. This case has given rise touseful discussions on the nature and value of errorestimation, and the best and clearest way of presentingthese complex ideas to our patients. We hope thatknowledge of this error will encourage more couples to optfor prenatal diagnosis following PGD.

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