Atopic dermatitis

PERIODIC

SYNOPSIS

Atopic dermatitis Eric L. Simpson, MD, and Jon M. Hanifin, MD Portland, Oregon

GENERAL REFERENCES Bieber T, Leung DYM. Atopic dermatitis. New York: Marcel Dekker; 2002. Leung DYM, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest 2004;113: 651-7. Rajka G. Essential aspects of atopic dermatitis. Berlin: SpringerVerlag; 1989. Williams HC. Atopic dermatitis—the epidemiology, causes and prevention of atopic eczema. Cambridge (UK): Cambridge University Press; 2000.

The 3 monographs can be useful sources for information on atopic dermatitis (AD). The text by Rajka, although much older, continues to be the most comprehensive general reference source. Among the newer texts, Bieber and Leung provide a more immunologically directed review, and Williams emphasizes epidemiological views. The recent journal review by Leung et al provides current information.

INTRODUCTION AD is a chronic inflammatory skin disease that usually occurs in persons with a personal or family history of other atopic conditions, such as asthma and allergic rhinitis. The prevalence is high, especially in children, and it has risen considerably in recent decades, leading to considerable epidemiological study. The past 30 years have also seen an enormous outpouring of laboratory investigations, primarily in the immunological realm. New concepts of causation have proliferated, whereas many old ones have regressed. It is interesting to look back at

From the Department of Dermatology, Oregon Health & Science University. This report reflects the best data available at the time the report was prepared, but caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations set forth in this report. Funding sources: None. Conflicts of interest: None identified. Correspondence to: Jon M. Hanifin, MD, Oregon Health & Science University, Department of Dermatology, 3181 SW Sam Jackson Park Rd, Portland, OR 97239-3098. E-mail: [email protected]. J Am Acad Dermatol 2005;53:115-28. 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.01.130

ideas that seem illogical now to appreciate that the same affinity for new and fashionable trends continues today in our confused and frustrated pursuit of clarity. This is especially true in the immunological realm where nearly every assay gives results that differ from normal controls. As a result, long lists of ‘‘abnormalities’’ have been described, but many are uninterpretable and perhaps meaningless because they were not subjected to comparisons with other eczemas or with other atopic conditions. It is impossible and uncritical in a ‘‘synopsis’’ to reference every paper describing defects in AD, but we have tried to select those that seem most relevant for continued study.

NOMENCLATURE Key points d Multifaceted uncertainty about AD terminology has developed in recent years, fixating mainly on IgE in the definition of atopy. d Most revised naming systems attempt to categorize patients with AD as ‘‘atopic’’ (or those with high total/specific IgE levels) and ‘‘non-atopic’’ (or those with normal levels of IgE). d Recently proposed names for those AD patients without elevated IgE levels or associated allergies include: d Atopiform dermatitis d Nonallergic dermatitis d Intrinsic AD d Nonallergic atopic eczema/dermatitis syndrome d Nonatopic eczema d Typical AD features without elevated IgE levels probably best describes pure AD and illustrates the fact that IgE is not a prerequisite for either the development or the diagnosis of this eczematous disease. Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 2004;113:832-6.

This committee has published the most recent example of a proposed naming system for AD based on IgE reactivity. As other studies have concluded (see Flohr et al given below), the presence or 115

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absence of IgE reactivity has little relevance in the diagnosis of AD or treatment of the skin disease. Hanifin JM. Atopiform dermatitis: do we need another confusing name for atopic dermatitis? Br Dermatol 2002;147:430-2.

Defining disease susbsets is valuable in AD gene linkage studies. However, applying different names to AD, depending on the presence or absence of IgE reactivity, does little to advance the diagnosis or treatment of this disease. Renaming AD to reflect IgE status implies to clinicians that IgE status alters the management of atopic skin disease, a view not substantiated by the literature. Flohr C, Johansson SGO, Wahlgren C-F, Williams H. How atopic is atopic dermatitis? J Allergy Clin Immunol 2004;114:150-8.

The literature regarding atopy, defined as the tendency to become sensitized and produce IgE antibodies, is reviewed as related to AD. The presence of atopy was found to have minimal value in the diagnosis or prognosis of AD. IgE may purely be an epiphenomenon and not an important pathogenic factor. This should serve as an example of why the definition of atopy needs to be re-examined. A more reliable and inclusive definition would recognize atopy as a genetically predisposed diathesis manifesting a variety of exaggerated responses—vasodilatation, reactive airways, pruritus, in addition to IgE overproduction—to a variety of environmental stimuli, including irritants, microbes, drugs, and allergens.

DIAGNOSIS Key points d The Hanifin-Rajka criteria remain a standard for the diagnosis of AD, although they are somewhat cumbersome for routine clinical use and too complex for epidemiological studies. d The United Kingdom Working Party criteria provide a validated instrument for epidemiological studies. Cultural factors may reduce its sensitivity in some areas of the world and nonspecific inclusion of patients with ichthyosis and familial atopy is a concern mitigating against its use for clinical and genetic cohort studies. Eichenfield LF, Hanifin JM, Luger TA, Stevens SR, Pride HB. Consensus Conference on Pediatric Atopic Dermatitis. J Am Acad Dermatol 2003;49:1088-95.

The 2001 American Academy of Dermatology (AAD) Consensus Conference suggested universal criteria for AD, more inclusive of infants and various ethnicities. Although not yet validated, they provide a reliable, abbreviated, practical set of criteria for the diagnosis of AD in all age groups.

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EPIDEMIOLOGY General reviews Schultz Larsen F, Hanifin J. Epidemiology of atopic dermatitis. Immunol Allergy Clin North Am 2002;22:1-24.

Defining AD for epidemiological studies is challenging. Questionnaires, although an efficient means of gathering data, can lack specificity and introduce bias. This review outlines the challenges of performing accurate epidemiological studies in AD. A critical look at the data pertaining to AD prevalence, time trends, and risk factors is presented. Williams HC. Epidemiology of atopic dermatitis. Clin Exp Dermatol 2000;25:522-9.

This article is a concise review of risk factors, natural course, and prevention of AD. Research gaps are identified, such as nonallergic mechanisms of AD development, disease severity measurements, adult AD studies, and studies of emollients in AD. Prevalence and distribution Williams HC, Robertson C, Stewart A, Ait-Khaled N, Anabwani G, et al. Worldwide variation in the prevalence of symptoms of atopic eczema. J Allergy Clin Immunol 1999;103:125-38.

There is great worldwide variation in the prevalence of AD, ranging from 0.6% to 20.5%. This large consortium evaluated 463,801 children from 56 different countries using self-reporting of the symptoms of AD. This study established the global geographic differences in AD prevalence with the general pattern of increasing prevalence with higher latitudes. Laughter D, Istvan J, Tofte S, Hanifin J. The prevalence of atopic dermatitis in Oregon schoolchildren. J Am Acad Dermatol 2000;43:649-55.

The prevalence of AD in the northwest region of the United States is 17.2%, similar to rates seen in northern Europe and in Japan. Yura A, Shimizu T. Trends in the prevalence of atopic dermatitis in school children: longitudinal study in Osaka Prefecture, Japan, from 1985 to 1997. Br J Dermatol 2001;145:966-73.

Studies published before 1993 have shown that the worldwide prevalence of AD has increased over the past 3 decades. This survey of 4 million primary school children in Osaka Prefecture confirmed an increase in AD lifetime prevalence from 15.0% to 24.1% between 1985 and 1997. Importantly, the increase seen in this study leveled off after 1993. Positive correlations of AD with higher social class and air pollution were confirmed. Muto T, Hsieh SD, Sakurai Y, Yoshinaga H, Suto H, Okumura K, et al. Prevalence of atopic dermatitis in Japanese adults. Br J Dermatol 2003;148:117-21.

The prevalence of adult AD is significant. This cross-sectional survey of 10,762 adults older than 30 years of age in Japan revealed point, 1-year,

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and lifetime prevalences of 2.9%, 3.0%, and 3.3%, respectively.

RISK FACTORS Key points d The prevalence of AD is higher in developed countries and urban areas, although the reasons are unclear. d AD is more prevalent in higher latitudes. d Migrant studies reveal that AD prevalence increases in populations that move from an area of low to high prevalence. These data support a role of environmental factors in the expression of AD. d The rate of AD increases show a correlation to higher social class, in contrast to many other chronic diseases. d Despite much research on cord blood IgE levels and other immunological markers, a family history of atopic disease remains the strongest predictor for the development of AD. d The cumulative data show no strong racial differences in the prevalence of AD. d Most studies confirm a slight female preponderance of AD. d Rural living and larger family size are protective factors in the development of AD. Early microbial exposure during infancy has been proposed as the underlying mechanism of these observations (‘‘hygiene hypothesis’’) Ben-Gashir MA, Seed PT, Hay RJ. Predictors of atopic dermatitis severity over time. J Am Acad Dermatol 2004;50:349-56.

Young age at onset, respiratory allergy, and urban living predict more severe disease. Benn CS, Melbye M, Wohlfahrt J, Bjorksten B, Aaby P. Cohort study of sibling effect, infectious diseases, and risk of atopic dermatitis during first 18 months of life. BMJ 2004;328:217-23.

The authors explore and dissect possible mechanisms behind the hygiene hypothesis. This cohort study of 13,070 children from Denmark showed no protective effect of early clinically detectable infections on the development of AD. Factors associated with microbial exposure such as farm residence, pet keeping, and day care did show a modest protective effect. This article suggests subclinical microbial exposures are protective factors against AD rather than overt infection. McIntire JJ, Umetsu SE, Macaubas C, Hoyte EG, Cinnioglu C, Cavalli-Sforza LL, et al. Hepatitis A virus link to atopic disease. Nature 2003;425:576.

Considerable interest has focused on the TH2 cytokine gene cluster in the region of 5q31-33, which shows association with increased IgE production. This study has suggested a link with TIM-1 on 5q33.2,

which, in susceptible individuals, binds hepatitis A virus, decreasing TH2 activity and protecting against asthma/atopy. This finding provides molecular support for the ‘‘hygiene hypothesis’’ speculations in which microbial factors are thought necessary to restore TH1/TH2 balance in protecting against atopy.

QUALITY OF LIFE Su JC, Kemp AS, Varigos GA, Nolan TM. Atopic eczema: its impact on the family and financial cost. Arch Dis Child 1997;76:159-62.

Having a child with moderate to severe AD affects a family more than having a child with type 1 diabetes mellitus. Ben-Gashir MA, Seed PT, Hay RJ. Quality of life and disease severity are correlated in children with atopic dermatitis. Br J Dermatol 2004;150:284-90.

Quality of life is reduced in 5- to 10-year-old children with AD and is related to disease severity. Schiffner R, Schiffner-Rohe J, Landthaler M, Stol W. Treatment of atopic dermatitis and impact on quality of life. A review with emphasis on topical non-corticosteroids. Pharmacoeconomics 2003;21:159-79.

Topical immunomodulators, topical steroids, phototherapy, and cyclosporine all have been shown to improve the quality of life in patients with AD. However, no comparisons have been made between therapeutic regimens. The authors conclude that there is only one answer to the question ‘‘Which treatment best improves quality of life in patients with AD?’’—we don’t know. A future research agenda is outlined.

COST OF CARE Lapidus CS, Schwarz DF, Honig PJ. Atopic dermatitis in children: who cares? who pays? J Am Acad Dermatol 1993;28:699-703.

Cost of care for patients in the United States with AD between 1990 and 1991 was estimated to be $364 million. Pharmaceuticals represented the largest expense. Expenditures for emergency department visits were very substantial. Better disease education and more frequent follow-up clinic visits may reduce the need for costly emergency department visits. Kemp AS. Cost of illness of atopic dermatitis in children—a societal perspective. Pharmacoeconomics 2003;21:105-13.

This article is a nice comprehensive review of data involving both the economic and societal costs of the disease. Ellis CN, Drake LA, Prendergast MM, Abramovits W, Boguniewicz M, Daniel R, et al. Cost of atopic dermatitis and eczema in the United States. J Am Acad Dermatol 2002;46:361-70.

In the United States, the economic cost of AD is similar to the cost of other chronic diseases, such as emphysema and epilepsy.

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GENETICS Key points d AD is a hereditary disease with high concordance in identical twin pairs. d There is also a familial association between AD and allergic respiratory disease. d Over the years, elevated IgE levels, asthma, and AD have been linked to almost every chromosome. d Phenotypic ascertainment varies considerably in different studies and undermines the reliability of some reports. d Many linkage projects have not focused on AD alone, but have included studies of respiratory atopy and IgE reactivity. Careful gene linkage studies may be able to distinguish which genes relate to the TH2/IgE component compared with those associated with the nonallergic variant of AD as a model for the specific eczematous disease. d Previous studies have shown colocalization of certain loci not only with AD, but with psoriasis, asthma, rheumatoid arthritis, and insulin-dependent diabetes mellitus. Lee Y-A, Wahn U, Kehrt R, Tarani L, Businco L, Gustafsson D, et al. A major susceptibility locus for atopic dermatitis maps to chromosome 3q21. Nat Genet 2000;26:470-3.

A northern European study indicated linkage at chromosome 3q21, suggesting possible candidate genes for CD80 and 86 (B7.1, B7.2) costimulatory molecules, which can interact with CD28/CTLA4 to mediate T-cell interactions. CD 80 and 86 candidate molecules serve a fundamental pathway of immune activation. Hummelshoj T, Bodtger U, Datta P, Malling HJ, Oturai A, Poulsen LK, et al. Association between an interleukin-13 promoter polymorphism and atopy. Eur J Immunogenet 2003;30:355-9.

This recent northern European study tested welldefined patient groups with allergy-associated AD, or with other atopic conditions. They confirmed two other reports of an association with the interleukin 13 (IL-13) gene promoter polymorphism in the 5q3133 cytokine cluster. The study suggested a C to T exchange localized to position e1024 and, in combining data from the 3 studies, demonstrated a strong association. Cookson WOCM, Ubhi B, Lawrence R, Abecasis GR, Walley AJ, Cox HE, et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat Genet 2001;27:372-3.

AD without asthma was identified on chromosome 1q21 and 17q25. In contrast, patients with AD and asthma, as well as those with asthma alone, mapped to chromosome 20p. This suggests AD without asthma may represent a different genetic subtype. As with previous linkage studies in AD,

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these loci mapped closely to psoriasis susceptibility loci. This group did not confirm the previous susceptibility locus on 3q21 found by Lee et al described above; however, it is likely several genes contribute to the full expression of AD. Becker KG, Barnes KC. Underlying disease specificity of genetic loci in atopic dermatitis. J Invest Dermatol 2001;117:1325-7.

Several studies have suggested shared linkages between AD and psoriasis at several loci. Other inflammatory and autoimmune diseases have mapped closely to loci identified in AD. Such colocalization may not be specific for AD, but rather it may define loci for common basic immunoregulatory mechanisms. Kato A, Fukai K, Oiso N, Hosomi N, Murakami T, Ishii M. Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Br J Dermatol 2003;148:655-69. Walley AJ, Chavanas S, Moffatt MF, Esnouf RM, Ubhi B, Lawrence R, et al. Gene polymorphism in Netherton and common atopic disease. Nat Genet 2001;29:175-8.

AD and IgE reactivity are two major components of Netherton disease. These two studies, from the United Kingdom and Japan, have shown the SPINK5 Netherton disease gene glu420lys polymorphism associated with AD. This gene codes for the LEKTI proteinase inhibitor, a defect of which might have considerable implication for inflammatory pathways relating to proteinase-activated receptors on keratinocytes and mast cells.

PATHOGENESIS Key points d Investigations of AD are replete with widely varied concepts of causation. d From the time of Besnier, we were given the concept that AD is the ‘‘itch that rashes.’’ From those early speculations came the concept (and the name) of neurodermatitis, which, in turn and in tandem with Freudian psychodynamics, led to the theory that AD was a disease of psychological instability. These represent only two from a long list of AD concepts that have come and gone through the past century. d Mast cell/histamine causation, IgE, eosinophils and TH2 cells are more recent causative conceptual entries, but all remain speculative and difficult to prove. d In contrast, if we consider those pathogenic aspects that are generally accepted as fact, we can assert that AD is: d An inflammatory skin disease d A strongly familial condition with genetic associations extending to allergic rhinoconjunctivitis and asthma d A disease that can be transferred by bone marrow cells

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The past few years have generated productive additions of studies in dendritic cells, keratinocytes, and neuroinflammatory elements. These developments are helping to increase awareness of other important pathogenic elements, in addition to the immunological anomalies, that contribute to the inflammation that is so relevant to AD. The widely disparate elements in AD pathogenesis force the consideration that a unifying, basic concept may be necessary to explain the many abnormal systems and that fundamental defects in signaling and regulatory pathways are a logical realm of investigation.

Signaling and regulation Key points d Pharmacophysiologic abnormalities, such as cholinergic hyperreactivity and reduced adrenergic responses were early indicators of altered cellular regulation in AD. d Mononuclear leukocyte cultures showed reduced cyclic AMP responses (caused by increased cAMPphosphodiesterase [PDE] hydrolysis), accounting for the inflammatory and immune hyperactivity characteristic of AD and other atopic diseases. d Increased PDE is found in umbilical cord blood cells of infants predisposed to AD. d PDE inhibitors correct the defect and reduce the overproduction of IgE, IL-4, IL-10, and other cytokines in cell cultures and have anti-inflammatory effects when applied topically to AD lesions. d More recent studies of signaling have focused on keratinocytes and on detailed pathways that have functional associations with cytokine production, interactions with immune/inflammatory pathways, and the induction of spongiosis and epidermal proliferation (see ‘‘Keratinocyte studies’’ below). d Development of T 2 immune responses is assoH ciated with abnormal regulation of cytokine and signaling pathways in keratinocytes. Proinflammatory cytokine gene expression is under control of transcription factors such as AP-1 and NF-kB whose synthesis and activation result from phosphorylation of kinases such as MAPK and ERK. d The MAP-kinase and other signaling pathways can mediate microbial stimulation of macrophage IL-12 production via toll-like receptors (TLRs), which in turn up-regulates the TH1 responses that are often deficient in AD. Girolomoni G, Pastore S. The role of keratinocytes in the pathogenesis of atopic dermatitis. J Am Acad Dermatol 2001;45(Suppl):S25-8.

This article provides a useful review for the important research realm of keratinocyte effects on

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inflammation in AD. Irritation or skin injury in AD triggers excessive keratinocyte production of granulocyte-macrophage colony-stimulating factor (GMCSF), IL-1, and tumor necrosis factor a (TNF-a). These factors may stimulate chemokines such as RANTES, which attract infiltrating immune and inflammatory cells, including T cells, monocytes, and eosinophils. The keratinocyte cytokines also activate and recruit dendritic cells, augmenting both innate and adaptive immune responses. Akdis CA, Akdis M, Trautmann A, Blaser K. Immune regulation in atopic dermatitis. Curr Opin Immunol 2000;12:641-6.

This article is an excellent, comprehensive review of the many facets of keratinocyte and immune interactions. Hanifin JM, Chan SC. Monocyte phosphodiesterase abnormalities and dysregulation of lymphocyte function in atopic dermatitis. J Invest Dermatol 1995;105(Suppl):84S-88S.

This article reviews previous work on the role of PDE in the dysregulation of immune and inflammatory cells in AD. Wild JS, Sur S. CpG oligonucleotide modulation of allergic inflammation. Allergy 2001;56:365-76.

This article reviews evidence for microbial CpG DNA activation of immune cells, the role of TLRs in initiating signaling pathways and the downstream expression of cytokines and other mediators that can enhance TH1 function. Keratinocyte studies Key points d A number of reports in recent years have begun to focus attention on the epidermis in AD. d Epidermal barrier abnormalities have great relevance to management of AD. d Recent studies into the mechanisms of spongiosis, the hallmark of AD, have focused on keratinocyte apoptosis mediated by T lymphocytes. d Keratinocytes in AD produce mediators that activate and regulate immune and inflammatory cells. Trautmann A, Akdis M, Kleeman D, Altmauer F, Simon HU, Graeve T, et al. T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenic role in eczematous dermatitis. J Clin Invest 2000;106:25-35.

Epidermal spongiosis represents the initial event in the development of the hallmark clinical feature of AD—the eczematous lesion. This study suggests a basic general mechanism for eczematization and barrier disruption in AD. Biopsy specimens from lesional AD or nickel allergic contact dermatitis (ACD) reactions showed keratinocyte apoptosis, which precedes spongiosis. In this in vitro system, interferon gamma (IFN-g) induced Fas receptor (Fas R) on keratinocytes. Activated T cells, or their

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supernatants containing soluble Fas ligand, initiated apoptosis. The requirements for T-cell activation and dependency on specific antigens are unclear. It highlights the importance of TH1/keratinocyte interactions in pathogenesis of eczematous lesions and provides a model for studies of signaling pathways in AD lesions. Warnnissorn P, Nakao A, Suto H, Ushio H, Yamaguchi N, Yagita H, et al. Tumour necrosis factor-related apoptosis-inducing ligand expression in atopic dermatitis. Br J Dermatol 2003;148:829-31.

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF-a family. TRAIL induces apoptosis in tumor cells and virus-infected cells. TRAIL-positive mononuclear cells are present in greater numbers in lesional skin of patients with AD compared with nonlesional AD skin, normal controls, and psoriasis lesional skin. TRAIL-positive macrophages may be specific to lesional skin and may mediate keratinocyte apoptosis. Iordanov MS, Sundholm AJ, Simpson EL, Hanifin JM, Ryabinina OP, Choi RJ, et al. Apoptosis-induced activation of epidermal growth factor receptor in keratinocytes: implications for restricting epidermal damage in dermatitis. J Invest Dermatol 2005 (in press).

This study confirms the development of apoptosis via the Fas signaling pathway, which in turn appears to initiate epidermal proliferation via the epidermal growth factor receptor in a human ACD model. Proliferation has been almost completely overlooked in basic studies of AD, yet the lichenification from keratinocyte proliferation that accompanies the chronic phase of AD is a major obstacle to successful topical therapy. These new studies have identified a cascade of possible molecular sites at which to target therapies to prevent spongiosis and to limit lichenification. Pastore S, Giustizieri ML, Mascia F, Giannetti A, Kaushansky K, Girolomoni G. Dysregulated activation of activator protein 1 in keratinocytes of atopic dermatitis patients with enhanced expression of granulocyte/macrophage-colony stimulating factor. J Invest Dermatol 2000;115:1134-43.

These authors have been at the forefront in identifying pathways by which keratinocytes may regulate downstream immune responses in AD. GMCSF overexpression and altered AP-1 regulation in keratinocytes from lesional AD skin may influence the presence of activated dendritic cells in the epidermis and dermis of AD skin. Elias PM, Feingold KR. Does the tail wag the dog? Role of the barrier in the pathogenesis of inflammatory dermatoses and therapeutic implications. Arch Dermatol 2001;137:1079-81.

The current treatment strategies in AD focus on T-cell inhibition as a means of normalizing the skin

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barrier. In contrast, the outside-in paradigm stresses the importance of stratum corneum dysfunction in driving cutaneous inflammation. Skin barrier repair approaches are discussed, but formal studies are needed to verify the importance of physiologic lipid replacement as a useful adjunctive treatment in AD. Hara J, Higuchi K, Okamata R, Kawashima M, Imokawa G. High expression of sphingomyelin deacylase is an important determinant of ceramide deficiency leading to barrier disruption in atopic dermatitis. J Invest Dermatol 2000;115:406-13.

Low stratum corneum ceramide levels may contribute to AD skin barrier dysfunction. Altered sphingomyelin metabolism in keratinocytes may account for this finding. The sphingomyelin deacylase-like enzyme appears to be overexpressed in AD skin, leading to a relative ceramide deficiency in the stratum corneum of AD skin. An alternative explanation may be that altered sphingomyelin metabolism is an epiphenomenon resulting from an altered signaling cascade that leads to spongiosis.

NEUROGENIC INFLAMMATION Key points d Neurogenic inflammation and/or itch can result from 3 main neurogenic mechanisms: d Autonomic neuromediators, such as acetylcholine, induce sweating and itch. d Neuropeptides (such as substance P and calcitonin gene-related peptide) released by cutaneous nerves and infiltrating immune cells can generate itch. d Proteinase-activated receptors (PARs) are emerging as the main mediators of itch in AD as opposed to histamine pathways. d Studies reveal atopic skin exhibits altered levels of nerve fibers, neuropeptides, neuropeptide receptors, and neuropeptidases. Steinhoff M, Stander S, Ansel JC, Schmelz M, Luger T. Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol 2003;139:1479-88.

This state-of-the-art review presents current facts and concepts relating to neuroinflammation and itch. Steinhoff M, Nisius U, Ikoma A, Fartasch M, Heyer G, Skov PS, et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci 2003;23:6176-80.

PARs are a new family of G-proteinecoupled receptors that become active after cleavage by proteases. PARs are found on sensory neurons, keratinocytes, mast cells, and endothelial cells. Four PARs have been molecularly identified, and PAR-2 appears to be an important mediator of neurogenic inflammation. PAR-2 agonists recruit leukocytes and cause pruritus and edema by stimulating

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the release of neuropeptides in peripheral tissues. PAR-2 and its endogenous ligand, mast cell tryptase, are increased in AD skin. Pruritus evoked via PAR2 activation is greater in patients with AD than in controls and is independent of histamine release. The authors conclude that PAR-2 signaling is an important link between the sensory nervous system and inflammation in AD. Katayama I, Bae S-J, Hamasaki Y-I, Igawa K, Miyazaki Y, Yokozeki H, et al. Stress response, tachykinin, and cutaneous inflammation. J Invest Dermatol 2001;6:81-6.

This mouse model delves into the mechanisms of stress-related itch and topical glucocorticoid withdrawal syndrome. Long-term use of glucocorticoids and endogenous glucocorticoids released under stressful conditions can alter skin reactivity via their effects on tachykinins.

IMMUNOLOGICAL FEATURES AD presents a complex immunological picture that can generally be considered to have two facets—immune deficiency and immune hyperresponsiveness. The pathogenic links between these two aspects are far from being clear, but considerable investigation has been proceeding in recent years. Immune deficiency Key points d Selective immune deficiency, at least in the skin, is reflected by the tendency of herpes simplex virus (HSV) and vaccinia to extend beyond typical margins and by the difficulty in sensitizing patients to Rhus and dinitrochlorobenzene. d Clinical experience suggests that patients also have more prolonged and extensive infections with warts and molluscum contagiosum. d Subnormal delayed hypersensitivity/contact allergy reactions in AD are assumed to be the general mechanistic explanation for the susceptibility to these cutaneous viral infections. d Interestingly, little is known about the pathogenic mechanisms underlying these deficient responses. Some possible explanations have emerged: d AD monocytes have increased production of IL-10 (a consequence of abnormal PDE activity), a cytokine that accentuates TH2 responses and inhibits TH1 cellular immune function. d IL-12 expression, considered important in stimulating IFN-a and other TH1 and proinflammatory factors, is reduced. d Regulatory T-cell abnormalities may damp the immune response against viral and other infections.

d

Reduced expression of defensins and other antimicrobial peptides (AMPs) may allow greater susceptibility to cutaneous infections in AD. Evidence indicates that excess IL-10 as well as TH2 cytokines may underlie the deficient AMP response.

Leung DYM, Howell MD. Elevated levels of IL-10 in intrinsic and extrinsic atopic dermatitis is associated with deficiency in antimicrobial peptide production [abstract]. J Allergy Clin Immunol 2004;113:S96.

This study confirms earlier work showing increased IL-10 expression and accounts for reduced AMP production in AD skin. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002;347:1151-60.

Antimicrobial protein defects in AD skin suggest another possible explanation for the altered skin infection susceptibility. Innate AMPs, defensins and cathelicidins, are deficient in the skin of patients with AD compared with psoriasis patients. Specificity is unclear because levels were comparable to those in normal skin, and this study lacked other eczema controls, though an earlier study from Sweden suggested similar levels in ACD. The findings are, however, novel and potentially exciting. Howell MD, Jones JF, Kisich KO, Streib JE, Gallo RL, Leung DYM. Selective killing of vaccinia virus by LL-37: implications for eczema vaccinatum. J Immunol 2004;172:1763-7.

The cathelicidin LL-37 inhibits the growth of the vaccinia virus in vitro. Knock-out mice lacking cathelicidins had more pox development after scarification with vaccina than control mice. Defensins had no effect on vaccinia growth. These findings present a possible mechanism for eczema vaccinatum. Wollenberg A, Zoch C, Wetzel S, Plewig G, Przybilla B. Predisposing factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases. J Am Acad Dermatol 2003;49:198-205.

Early age at AD onset and total IgE levels correlate to a higher risk of development of eczema herpeticum (EH). The use of corticosteroids does not increase the risk of developing EH, and undertreated areas are the likely sites of involvement. Immune hyperresponsiveness Key points d Activated T cells reside in lesional skin of patients with AD. Activation of T cells may occur from many sources. Irritants stimulating keratinocyte responses may be the most prevalent initiator, and superantigens and allergens are also considered possible sources of activation.

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There are increased TH2 responses in skin, blood, and lymph nodes that contribute to the respiratory allergy and food allergy that often accompanies AD. AD monocytes and dendritic cells have increased production of IL-10, a cytokine that inhibits TH1 function and accentuates TH2 responses. Viewing AD as a purely TH2-mediated disease, however, oversimplifies this immunologically complex disease as T cells from skin of chronic lesions have been shown to express a TH1-skewed cytokine profile. A popular working hypothesis suggests the presence of a TH2-stimulated ‘‘acute’’ response followed by a switch to TH1-mediated ‘‘chronic’’ inflammation. A weakness of this concept is the strong, conflicting evidence (cited above) for IFNgestimulated Fas initiation of eczema. The study of regulatory T cells in AD and atopic diseases is only in the early stages, and one regulatory mechanism, IL-10, is confused by the prominent monocyte IL-10 overexpression in AD. The relative contributions of T cells and monocytes and their relevance to atopic immune regulation remain to be delineated.

Grewe M, Bruijnzeel-Koomen CAFM, Schopf E, Thepen T, Langeveld-Wildschut AG, Ruzicka T, et al. A role for Th1 and Th2 cells in the immunopathogenesis of atopic dermatitis. Immunol Today 1998;19:359-61.

This article is a review of studies suggesting that, in allergen patch tests, early reactions are TH2 mediated and later, the responses have TH1 characteristics. Santamaria Babi LF, Picker LJ, Perez Soler MT, Drzimalla K, Flohr P, Blaser K, et al. Circulating allergen-reactive T cells from patients with atopic dermatitis and allergic contact dermatitis express the skin-selective homing receptor, the cutaneous lymphocyteassociated antigen. J Exp Med 1995;181:1935-40.

Although not specific for AD, CLA1 T cells bind endothelial E-selectin and are prominent in AD lesions. Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J, et al. Relation of CD41CD251 regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 2004;363:608-15. Ou L-S, Goleva E, Hall C, Leung DYM. T regulatory cells in atopic dermatitis and subversion of their activity by superantigens. J Allergy Clin Immunol 2004;113:756-63.

Regulatory T cells (Tregs, CD41CD251 T cells, known in the past as suppressor T cells) may be increased in AD, though evidence appears to be conflicting in these two studies; decreased Treg activity was reported in atopic individuals without AD.

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Hijnen D, de Bruin-Weller M, Oosting B, Lebre C, de Jong E, Bruijnzeel-Koomen C, et al. Serum thymus and activationregulated chemokine (TARC) and cutaneous T cell-attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis. J Allergy Clin Immunol 2004;113:334-40.

Serum levels of the T-cell chemokine thymus and activation-regulated chemokine (TARC; CCL-17) are greatly elevated in AD and apparently correlate with disease severity. Whether this is a specific marker for AD awaits ACD comparison, but an appealing scenario suggests that TARC might initiate T-cell recruitment to the dermoepidermal junction where these cells interact with keratinocytes to trigger apoptosis/ spongiosis. Dendritic cells Key points d Dendritic cells (DCs) are prominent in the epidermis and in the cellular infiltrates of AD. Studies have demonstrated several features that suggest a role for DCs in the pathogenesis of AD. d Increased IgE-bearing DCs (FceRI) in AD skin may amplify TH2 responses to antigens passing through the epidermis. d Monocyte survival is increased in patients with AD. d Inflammatory dendritic epidermal cells may augment TH1-associated eczema. d High monocyte IL-10, low IL-12 may account for reduced TH1 immunity and for exaggerated TH2 responses. Bieber T. Fc epsilon RI-expressing antigen-presenting cells: new players in the atopic game. Immunol Today 1997;18:311-3.

This review of the identification of the highaffinity receptor of IgE (FceRI) on the surface of monocytes and dendritic cells helped clarify the role and relevance of variable expression on different antigen-presenting cells. Wollenberg A, Mommaas M, Oppel T, Schottdorf EM, Gunther S, Moderer M. Expression and function of the mannose receptor CD206 on epidermal dendritic cells in inflammatory skin diseases. J Invest Dermatol 2002;118:327-34.

A dendritic cell subset with distinct markers, inflammatory dendritic epidermal cells, is present in lesional AD sites and may enhance TH1 eczematous responses. Allam J-P, Klein E, Bieber T, Novak N. Transforming growth factorb1 regulates the expression of the high-affinity receptor for IgE on CD341 stem cell-derived CD1a1 dendritic cells in vitro. J Invest Dermatol 2004;123:676-82. Lee HJ, Lee HP, Ha SJ, Byun DG, Kim JW. Spontaneous expression of mRNA for IL-10, GM-CSF, TGF-beta, TGF-alpha, and IL-6 in peripheral blood mononuclear cells from atopic dermatitis. Ann Allergy Asthma Immunol 2000;84:553-8.

Subnormal transforming growth factoreb levels in blood and tissues of patients with AD may

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influence FceRI expression and differentiation of dendritic cells. Mast cells and histamine Key points d There is conflicting evidence for increased mast cells and histamine in AD lesions, but most studies that showed an increase were not controlled. d Studies of psoriasis, lichen planus, and other chronic inflammatory skin conditions showed similarly increased mast cell numbers, suggesting that these are nonspecific inflammatory accompaniments. d A direct histamine role in eczematization and AD itch remains speculative. (Hanifin JM. [1992] Do mast cells play a role in atopic dermatitis? In: Kaliner M, Metcalfe D, editors. The mast cell in health and disease. New York: Marcel Dekker; 1992. p. 639-51). d

Antihistamines are ineffective in treating AD.

Akdis CA, Blaser K: Histamine in the immune regulation of allergic inflammation. J Allergy Clin Immunol 2003;112:15-22. Van der Pouw Kraan TCTM, Snijders A, Boeije LCM, de Groot ER, Alewijnse AE, Leurs R, et al. Histamine inhibits the production of interleukin-12 through interaction with H2 receptors. J Clin Invest 1998;102:1866-73.

d

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Their role has been widely investigated in the cutaneous late-phase reaction (LPR) to injected allergens; however, the LPR has little resemblance to AD and its relevance is unclear. Human studies have demonstrated that systemic therapy with anti-IL-5 reduces eosinophilia, but have shown little clinical effect. Recent studies in human asthma, as well as in murine models, have cast doubt on the inflammatory role of eosinophils and have tended to shift focus to connective tissue remodeling.

Ott NL, Gleich GJ, Peterson EA, Fujisawa T, Sur S, Leiferman KM. Assessment of eosinophil and neutrophil participation in atopic dermatitis: comparison with the IgE-mediated late-phase reaction. J Allergy Clin Immunol 1994;94:120-8.

This is an important study reviewing evidence for eosinophil participation in AD inflammation and distinguishing characteristics of AD from those of the LPR. Beck LA, Leung DYM. Allergen sensitization through the skin induces systemic allergic responses. J Allergy Clin Immunol 2000;106(Suppl):S258-63.

This article offers a good review of allergy/immunology aspects of AD with special emphasis on the role of eosinophils.

Histamine may influence immune/inflammatory regulation through H2 receptors to inhibit IL-12 and increase IL-10.

Phipps S, Flood-Page P, Menzies-Gow A, Ong YE, Kay AB. Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin deposition in allergen-challenged human atopic skin. J Invest Dermatol 2004;122:1406-12.

Giustizieri ML, Albanesi C, Fluhr J, Gisondi P, Norgauer J, Girolomoni G: H1 histamine receptor mediates inflammatory responses in human keratinocytes. J Allergy Clin Immunol 2004;114:1176-82.

Anti-IL-5, given intravenously, decreases eosinophils in asthma and AD but has little effect on clinical disease. In experimentally induced human LPRs, anti-IL-5 greatly lowers eosinophil levels but does not reduce the size of the reaction.

Histamine may act on keratinocytes via the H1 receptor to amplify inflammatory T-cell reactions. Schecter NM, Brass LF, Lavker RM, Jensen PJ. Reaction of mast cell proteases tryptase and chymase with protease activated receptors (PARs) on keratinocytes and fibroblasts. J Cell Physiol 1998;176:365-73.

Mast cell tryptase may cleave PARs to trigger neurogenic inflammation. Eosinophils Key points d Eosinophils contain abundant quantities of cationic granule proteins including major basic protein, eosinophil cationic protein, eosinophilderived neurotoxin, and eosinophil peroxidase. All can cause injurious microbial and tissue effects, and deposition has been demonstrated in AD lesions. d These cells might be important effectors in AD, though they are not specific and are present in a wide variety of cutaneous inflammatory disorders.

Wills-Karp M, Karp CL. Eosinophils in asthma: remodeling a tangled tale. Science 2004;305:1726-9.

This article reviews new information questioning the pathogenic role of eosinophils in skin and bronchial inflammation and suggesting they may relate more to subepithelial remodeling, not generally considered germane to AD.

FLARE FACTORS Microbes Key points d Viral upper respiratory tract infections represent the most common and consistent flare factor in infants and children; however, little is known about the mechanism. d Staphylococcal infection as a trigger for AD has been an active area of research for more than 3 decades since the finding that more than 90% of adult patients are colonized with Staphylococcus aureus.

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Superantigens have been a focus of considerable research as a mechanism to explain T-cell activation in AD. It has been an attractive concept but overzealously promoted, with many uncontrolled studies and indications that the same findings may apply to various inflammatory skin diseases as well as to normal skin.

Akdis M, Simon H-U, Weigl L, Kreyden O, Blaser K, Akdis CA. Skin homing [cutaneous lymphocyte-associated antigen-positive] CD81 T cells respond to superantigen and contribute to eosinophilia and IgE production in atopic dermatitis. J Immunol 1999;163:466-75.

CD41T cells are thought to be the key effector cells in driving TH2 inflammation in AD. This work revealed that, as with CD41 cells, CD81 T cells in patients with AD also respond to superantigens and secrete high levels of TH2 cytokines. Psychological stress Garg A, Chren MM, Sands LP, Matsui MS, Marenus KD, Feingold KR, et al. Psychological stress perturbs epidermal permeability barrier homeostasis: implications for the pathogenesis of stress-associated skin disorders. Arch Dermatol 2001;137: 53-9.

Psychological stress was shown in the 1950s to cause rapid-onset clinical itch/scratch responses in AD subjects. Previous mouse models have shown that psychological stress also negatively affects skin barrier function. In this study, the ability to repair the skin barrier was diminished in students during final examinations as compared with school vacation periods. Exacerbation of skin diseases, such as AD, by psychological stress may be explained by perturbations of skin barrier function. Allergy and IgE Key points d Immunological conceptualizations centered on allergy have dominated research in AD over the past 25 years, outnumbering other investigative areas by a large ratio. Frequently positive radioallergosorbent tests (RASTs) and skin prick tests are described to patients as ‘‘allergies.’’ d Allergy is defined as an adverse health effect that results from stimulation of a specific immune response. Failure to adhere to this definition results in enormous misinformation that confuses patients and other physicians. d True IgE-mediated allergies are clearly more frequent in AD, and it is important to recognize clinically significant immediate urticarial and respiratory symptoms/reactions to foods or inhalants. These carry a risk of anaphylaxis and, even when mild, may initiate stress-induced itching that can worsen an eczematous condition.

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Tan BB, Weald D, Strickland I, Friedmann PS. Double-blind controlled trial of effect of housedust-mite allergen. Lancet 1996;347:15-8.

This study showed that the severity of AD decreased after house dust mite reduction compared with control subjects using sham mite reduction procedures. This study was well performed; however, these positive results have been offset by several subsequent negative studies in both children and adults using dust mite reduction strategies. Beltrani V, Hanifin J. Atopic dermatitis, house dust mites, and patch testing. Am J Contact Dermatitis 2002;13(June):80-2.

‘‘Pro’’ and ‘‘con’’ arguments are laid out regarding the importance of dust mite allergens and dust mite patch testing in the pathophysiology and treatment of AD. The allergist perspective points to studies of AD exacerbation after inhaled protein challenge. The alternative view cites the lack of well-controlled studies linking dust mite to AD flares. In fact, most patients with AD have disease reduction in tropical climates where dust mite populations are highest.

RESPIRATORY ATOPY AND THE ATOPIC MARCH Key points d The atopic march refers to the sequential development of AD, allergic rhinitis, and asthma. Longitudinal studies reveal that AD is a risk factor for the future development of allergic airway disease. d The risk of the development of asthma correlates to the severity of AD. d Animal models suggest epicutaneous exposure to protein antigens can lead to allergen sensitization, excess IgE production, and allergic airway disease. d Long-term studies now under way will assess whether more aggressive treatment of AD during infancy might later reduce the impact of asthma and allergies. Spergel JM, Mizoguchi E, Brewer JP, Martin TR, Bhan AK, Geha RS. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest 1998;101:1614-22.

Epicutaneous sensitization leads to respiratory hyperresponsiveness in a mouse model. This is an important study linking skin sensitization and respiratory allergy. Herrick CA, MacLeod H, Glusac E, Tigelaar AE, Bottomly K. Th2 responses induced by epicutaneous or inhalational protein exposure are differentially dependent on IL-4. J Clin Immunol 2000;105:765-75. Herrick CA, Xu L, McKenzie AN, Tigelaar RE, Bottomly K. IL-13 is necessary, not simply sufficient, for epicutaneously induced Th2 responses to soluble protein antigen. J Immunol 2003;170:2488-95.

In this murine model, IgE levels were 100- to 1000fold higher when antigen was given epicutaneously

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versus the nasal route. The skin is a potent site for TH2-mediated sensitization to protein antigens, but is independent of IL-4 in contrast to respiratory sensitization models. IL-13, structurally related to IL-4, appears to be the major mediator driving TH2 responses during epicutaneous sensitization.

FOOD ALLERGY Key points d Type I urticarial reactions probably occur in approximately one third of patients with AD, though these are usually from tertiary centers seeing patients with severe disease. d Positive food allergy tests are common in children with AD, but skin prick testing and RASTs poorly predict actual food reactions in patients. d The clinical relevance of food allergy to the worsening of eczematous lesions in AD is controversial. Studies regarding eczematous reactions are hampered by the difficulty of differentiating early- from late-phase reactions in a disease characterized by frequent fluctuations in disease severity. d There are no good data to support the routine use of elimination diets as adjunctive therapy in AD if no clinical evidence of type I reactions have occurred. Lack G, Fox D, Northstone K, Golding J. Factors associated with the development of peanut allergy in childhood. N Engl J Med 2003;348:977-85.

This article reports a study performed by allergists discounting maternal diet as a contributing factor to the development of peanut allergy. Furthermore, the strongest predictive factor for the development of peanut allergy was a history of application of peanut oil to inflamed skin. This provides further evidence, albeit indirect, that epicutaneous IgE sensitization may play a role in allergic diseases. Sampson H, Ho DG. Relationship between food-specific IgE concentration. J Allergy Clin Immunol 1997;100:444-51. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891-6.

A retrospective analysis of RAST levels of foodspecific IgE to egg, milk, peanut, and fish was performed as compared with double-blind, placebo-controlled food challenges. RAST threshold levels were determined for predicting with 95% confidence a clinically relevant immediate food reaction. These cut-off values were then used to prospectively analyze 100 consecutive children and showed very good positive predictive values, but lower sensitivities. These cut-off values provide an alternative to double-blind, placebo-controlled food

challenges and help clinicians counsel patients when confronted with elevated food-specific IgE levels.

THERAPY General references Hanifin JM, Cooper KD, Ho VC, Kang S, Krafchik BR, Margolis DJ, et al. Guidelines of care for atopic dermatitis. J Am Acad Dermatol 2004;50:391-404. [www.eblue.org] Hoare C, Li Wan Po A, Williams H. Systematic review of treatments for atopic eczema. Health Technol Assess 2000;4:1-191.

The key points throughout this section were synthesized primarily from the summary findings of these two exhaustive evidence-based reviews of therapies for AD. They are invaluable resources for any practitioner treating patents with AD. Topical corticosteroids Key points d Topical steroids continue to be the mainstay of AD therapy, although there is a paucity of data that examine the effects of prolonged topical steroid use on the growth curve and bone-density of children. d An effective general strategy to skin management is as follows: d Step 1. Induction of remission d Step 2. Stabilization and maintenance d Step 3. Rescue of flares d Rapid flares of AD are best treated with 5 to 7 days of a medium- to high-potency topical corticosteroid ointment. The goal of this approach is to induce partial remission of disease activity. Safer long-term topical maintenance strategies then must follow this induction phase. Hanifin JM, Gupta AK, Rajagopalan R. Intermittent dosing of fluticasone propionate cream for reducing the risk of relapse in atopic dermatitis patients. Br J Dermatol 2002;147:528-37.

This study introduces a long-term maintenance treatment strategy for AD, based on inducing remission with twice-daily fluticasone cream, then using twice-weekly corticosteroid as maintenance to areas of skin previously affected. This is a safe and effective method of using corticosteroids once disease activity has been stabilized. Thomas KS, Armstrong S, Avery A, Li Wan Po A, O’Neill C, Young S, et al. Randomised controlled trial of short bursts of a potent topical corticosteroid versus prolonged use of a mild preparation for children with mild or moderate atopic eczema. BMJ 2002;324:768.

Shorter periods of medium-potency topical corticosteroid use are as effective as a longer course of low-potency corticosteroids in controlling AD flares. This approach can minimize the time patients are exposed to topical steroids. Maintenance therapy follows once disease has been stabilized.

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Topical calcineurin inhibitors Key points d Tacrolimus and pimecrolimus are safe and effective in reducing the severity of AD symptoms in children and adults. d Tacrolimus has a favorable safety profile for up to 4 years of use d Tacrolimus and pimecrolimus are useful for maintenance therapy after establishing acute control of disease flares with topical corticosteroids. d The calcineurin inhibitors are especially helpful in head and neck dermatitis where steroid use should be limited. (Hanifin JM, Paller A, Eichenfield L, Clark R, Korman N, Weinstein G, et al. Long-term (up to 4 years) efficacy and safety of tacrolimus ointments in patients with atopic dermatitis. J Am Acad Dermatol 2005 (in press).) Iskedjian M, Piwko C, Shear N, Langley RG, Einarson TR. Topical calcineurin inhibitors in the treatment of atopic dermatitis: a meta-analysis of current evidence. Am J Clin Dermatol 2004;5:267-79.

Success rates are similar for tacrolimus and pimecrolimus in the treatment of AD. No comparison of efficacy can be made without head-to-head studies, but tacrolimus studies generally involved patients with more severe disease than pimecrolimus studies did. This article is a good review of all randomized controlled trials involving the two available calcineurin inhibitors. Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, et al. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pedatrics 2002;110(1 pt 1):e2. Pimecrolimus cream used for the first signs and symptoms of AD significantly reduced disease flares and corticosteroid use. This study serves as a model for relapse prevention strategies using calcineurin inhibitors. Nakahara T, Koga T, Fukagawa S, Uchi H, Furue M. Intermittent topical corticosteroid/tacrolimus sequential therapy improves lichenification and chronic papules more efficiently than intermittent topical corticosteroid/emollient sequential therapy in patients with atopic dermatitis. J Dermatol 2004;31:524-8.

Although the study was unblinded, the authors examined the idea of combining topical immunomodulators with intermittent topical steroids to improve clinical outcomes and reduce the adverse effects of long-term steroid use. Subjects were treated with topical steroid 4 days per week and tacrolimus ointment 3 days per week. The combination treatment showed greater improvement in long-term AD lesions than intermittent steroids alone. Phototherapy Key points d Broadband UVA and UVB, narrowband UVB, combination UVAB, oral and bath psoralen

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plus ultraviolet A (PUVA), and UVA1 have all shown clinical safety and efficacy in the treatment of AD. One study has shown narrowband UVB to be as effective as bath PUVA in AD

(Der-Petrossian M, Seeber A, Honigsmann H, Tanew A. Half-side comparison study on the efficacy of 8-methoxypsoralen bathPUVA versus narrow-band ultraviolet B phototherapy in patients with severe chronic atopic dermatitis. Br J Dermatol 2000;142:39-43). d

Studies are needed in comparison of narrowband UVB to broadband UVB, UVAB, and to UVA1.

Scheinfeld NS, Tutrone WD, Weinberg JM, DeLeo VA. Phototherapy of atopic dermatitis. Clin Dermatol 2003;21:241-8.

This article provides a good overall review of phototherapy for AD. Reynolds NJ, Franklin V, Gray JC, Diffey BL, Farr PM. Narrow-band ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomized controlled trial. Lancet 2001;357:2012-6.

Narrowband UVB is safe and effective for the adjunctive treatment of moderate to severe AD and is more effective than broadband UVA. Krutmann J, Diepgen TL, Luger TA, Grabbe S, Meffert H, Sonnichsen N, et al. High-dose UVA1 therapy for atopic dermatitis: results of a multicenter trial. J Am Acad Dermatol 1998;38:589-93.

UVA1 is more effective in controlling AD than UVAB combination therapy and medium-potency topical steroids. UVA1 is emerging as a new therapy for acute flares of AD. The utility of UVA1 is hindered by the high temperatures generated during treatment, which can be intolerable to patients. Cooling systems have been devised to improve tolerability and may improve efficacy. Systemic therapy Patients with severe AD frequently have a disabling chronic condition that requires aggressive, definitive therapy both to induce remission and to maintain control. As an example, phototherapy, both for onset and duration of effectiveness, is greatly aided by remittive systemic therapy. Oral or intramuscular corticosteroids are neither safe nor practical except for brief, 1-week courses to control acute crises. Safer systemic therapy for prolonged control—the obvious need in a chronic condition like AD—is best achieved with other immunosuppressants. Sidbury R, Hanifin J. Systemic therapy for atopic dermatitis. Clin Exp Dermatol 2000;25:559-66.

A comprehensive review of agents and strategies for managing difficult AD is presented.

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Akhavan A, Rudikoff D. The treatment of atopic dermatitis with systemic immunosuppressive agents. Clin Dermatol 2003;21:225-40.

Clinical guidelines are created in this review for the safe and effective use of cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, and interferon gamma as systemic therapies for AD.

Cyclosporine Key points d Cyclosporine is the best-studied immunosuppressant for the treatment of AD. d Several studies have proven its safety and efficacy in the treatment of adult and childhood AD. d Hypertension and renal toxicity limit the continuous use of cyclosporine, except in patients with the most severe disease. d Dose levels of 5 mg/kg are usually necessary to induce remission of AD in patients with severe disease for whom cyclosporine is appropriate. Berth-Jones J, Graham-Brown RA, Marks R, Camp RD, English JS, Freeman K, et al. Long-term efficacy and safety of cyclosporine in severe adult atopic dermatitis. Br J Dermatol 1997;136: 76-81.

Intermittent, 12-week courses of cyclosporine serve as an alternative strategy to continuous therapy and have been shown to be more effective than UVAB phototherapy.

Azathioprine Key points d Generally, the middling responses, along with high incidence of adverse events, place this therapy behind cyclosporine in the therapeutic ladder for severe AD. d Onset of effect is slow and patients are often discouraged by the prolonged course with effects that are not dramatic. d As with use in bullous disease, dosing should be adjusted according to thiopurine methyltransferase genotype/levels. Berth-Jones J, Takwale A, Tan E, Barclay G, Agarwal S, Ahmed I, et al. Azathioprine in severe adult atopic dermatitis: a doubleblind, placebo-controlled, crossover trial. Br J Dermatol 2002;147:324-30.

This randomized, placebo-controlled study confirmed the efficacy of azathioprine as adjunctive treatment for AD seen in previous open-label studies. Clinical scores improved by 26% in the azathioprine group versus 3% in the placebo group (P \ .01). Gastrointestinal disturbances were common with this treatment. Blood cell counts and liver function tests need to be followed closely.

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Mycophenolate mofetil Grundmann-Kollman M, Podda M, Ochsendorf F, Boehncke W-H, Kaufmann R, Zollner TM. Mycophenolate mofetil is effective in the treatment of atopic dermatitis. Arch Dermatol 2001;137:870-3.

This inhibitor of purine synthesis decreased clinical scores by more than 50% in an open-label study of 10 adults with AD. The majority of patients had a prolonged remission as measured at the 12-week follow-up time point. Mycophenolate mofetil adds an immunosuppressant to the AD treatment armamentarium with a better safety profile than cyclosporine or azathioprine, but controlled studies are needed to prove efficacy. Interferon gamma Key points d This therapy, given by daily subcutaneous injection at bedtime, can provide rapid and lasting benefit. d The expense of IFN-g limits its use, but for patients with severe disease for whom cyclosporine therapy failed, it can be a welcome alternative. d Once stabilized, some patients can be maintained on alternate-day or once-weekly dosing. Stevens SR, Hanifin JM, Hamilton T, Tofte SJ, Cooper KD. Longterm effectiveness and safety of recombinant human interferon-gamma therapy for atopic dermatitis despite unchanged serum IgE levels. Arch Dermatol 1998;134:799-804.

Treatment effectiveness can be maintained with up to 2 years of continuous therapy. Improvement in skin scores were seen despite no changes in IgE levels. Eosinophils were reduced in this study, indicating a TH2 to TH1 switch likely was occurring in AD immunocytes. This study highlights the importance of cellular immune defects, over humoral defects, as the most important driving force in AD. Anti-IgE therapy Key points d A humanized antibody, omalizumab, has less than 5% murine composition and has been marketed for allergic asthma, usually given as monthly injections. d Questions arise as to its potential for AD but there is no evidence for an IgE role in eczema, and generally the total IgE levels in AD are too high to be neutralized. Antihistamines and leukotriene inhibitors Key points d Although they do not have direct effects on the pruritus associated with AD, sedating antihistamines can be helpful to improve sleep in flaring

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patients and to reduce symptoms of accompanying respiratory allergy. Leukotriene inhibitors, developed for asthma, have received considerable word-of-mouth testimonial support, and a few unblinded trials have been reported; however, negative results have been associated with controlled trials, which seldom get reported.

Klein PA, Clark RA. An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch Dermatol 1999;135:1522-5.

This evidenced-based review of the literature found no evidence to support the effectiveness of nonsedating antihistamines in the treatment of AD. Miscellaneous treatments Key points d There is no definitive evidence that routine diet restriction or allergen avoidance has a role in the treatment of AD except in cases where acute clinically relevant reactions have occurred. d No therapeutic value has been proven for dietary supplementation or alternative therapy for AD. d Preliminary studies of massage therapy, hypnotherapy, and biofeedback have been encouraging. Van Gool CJAW, Zeegers MPA, Thijs C. Epidemiology and health services research oral essential fatty acid supplementation in atopic dermatitis—a meta-analysis of placebo-controlled trials. Br J Dermatol 2004;150:728-40.

This meta-analysis of oral fatty-acid replacement studies concluded they provided no improvement.

NURSING Cork MJ, Britton J, Butler L, Young S, Murphy R, Keohane SG. Comparison of parent knowledge, therapy utilization and severity of atopic eczema before and after explanation and demonstration of topical therapies by a specialist dermatology nurse. Br J Dermatol 2003;149:582-9.

This study underscores the need for patient education regarding the disease and treatments. Caregivers have difficulty remembering the relevant potencies of topical steroids and therapy is compro-

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mised unless patients and/or family members have good understanding. Hanifin JM, Tofte SJ. Patient education in the long-term management of atopic dermatitis. Dermatol Nursing 1999;11:284-9.

The key to successful treatment of AD lies in disease education and compliance with topical therapies. No patient with AD should leave your office without understanding the concepts discussed in this practical review. This article is a must for nursing staff who help care for patients with AD.

PREVENTION Key points d No good evidence exists for primary prevention of AD except one controlled study of perinatal lactobacillus cultures. d Moisturizers can improve the barrier function in patients with AD and serve as an important secondary prevention measure. Few data exist on the types of moisturizers that are most effective for this purpose. d Studies regarding breastfeeding as a primary preventive measure in AD have not shown a consistent protective effect. Kalliomaki M, Salminen S, Poussa T, Arvilommi H, Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomized placebo-controlled trial. Lancet 2003; 361:1869-71.

The preventive effects of probiotics on AD appear to extend beyond infancy. This follow-up study revealed a relative risk of 0.57 (confidence interval 0.33-0.97) for the intervention group at 4 years. In other words, probiotics cut the risk of developing AD in half. Skin prick test reactivity showed no differences between groups. Heine RG, Hill DJ, Hosking CS. Primary prevention of atopic dermatitis in breast-fed infants: what is the evidence? J Pediatr 2004;144:564-7.

After reviewing all RCTs involving breastfeeding as primary prevention, the authors conclude breastfeeding during the first 4 months has a protective effect when compared with cow’s milk, but on its own does not constitute an effective prevention strategy.