You are on page 1of 30

A newer version of UpToDate is now available, and the information in this version may no longer be current.

Epidemiology, clinical manifestations, and diagnosis of atopic dermatitis (eczema)

Authors William L Weston, MD William Howe, MD Section Editors Robert P Dellavalle, MD, PhD, MSPH Moise L Levy, MD Joseph Fowler, MD Deputy Editor Rosamaria Corona, DSc, MD

Last literature review version 19.1: January 2011 | This topic last updated: February 10, 2011 (More)

INTRODUCTION Atopic dermatitis is a chronic inflammatory skin condition that appears to involve a genetic defect in the proteins supporting the epidermal barrier. Atopy, referring to "out of place", describes a group of disorders that include eczema, asthma, and allergic rhinitis [1]. However such a link between atopic dermatitis and asthma and hay fever has been called into question and is now controversial [2-4]. (See "Risk factors for asthma", section on 'Atopy'.)

The terms "dermatitis" and "eczema" are frequently used interchangeably. When the term "eczema" is used alone, it usually refers to atopic dermatitis (atopic eczema). "Eczematous" also connotes some crusting, serous oozing, or blister formation as opposed to mere erythema and scale.

The epidemiology, pathogenesis, clinical manifestations, and diagnosis of atopic dermatitis are reviewed here. The treatment of atopic dermatitis, the impact of staphylococcus aureus and other microbes on atopic dermatitis, the role of allergy in atopic dermatitis, and a review of other types of dermatitis are discussed separately. (See "Treatment of atopic dermatitis (eczema)" and "Management of severe refractory atopic dermatitis (eczema)" and "Role of allergy in atopic dermatitis (eczema)" and "Overview of dermatitis".)

EPIDEMIOLOGY Atopic dermatitis affects approximately 5 to 20 percent of children worldwide [5]. The prevalence of atopic dermatitis in the United States is around 11 percent [6].

The incidence of atopic dermatitis appears to be increasing. It may occur in any race or geographic location, although there appears to be a higher incidence in urban areas and developed countries, especially western societies [6,7].

The vast majority of atopic dermatitis has an onset before age five years, and prevalence data in children show a slight female to male preponderance (1.3 to 1) [8].

PATHOGENESIS Two major models currently exist to explain the pathogenesis of atopic dermatitis. The predominant model describes atopic dermatitis as a result of impaired epidermal barrier function due to intrinsic structural and functional abnormalities in the skin. In this model, the disease evolves from the outside in, with an abnormal epidermal barrier as the primary defect [9]. The second and traditional model views atopic dermatitis as primarily an immune function disorder in which Langerhans cells, T-cells and immune effector cells modulate an inflammatory response to environmental factors. While widely accepted for years, there is now little support that atopic dermatitis is the result of allergies [2-4].

Epidermal permeability barrier The epidermis is the first line of defense between the body and the environment. An intact epidermis keeps environmental irritants, allergens, and microbes from entering the body [10]. Permeability of the epidermis is determined by complex interactions of differentiated keratinocytes on the surface of the skin called corneocytes and groups of structural proteins, such as filaggrin, regulatory enzymes, and lipids [11]. Any disruption of these components through inherited defects, trauma, decreased humidity, alteration of pH, and infection can interfere with the ability of the epidermis to function as an effective barrier. Disruption allows antigenic and irritant agents to penetrate

the barrier and come into contact with immune cells, leading to the release of proinflammatory mediators [11]. This can then produce the clinical and pathologic findings of dermatitis.

Epidermal hydration Hydration of the epidermis is a key factor in maintaining an intact barrier, and the stratum corneum layer of the epidermis plays a key role in the retention of water in the skin. Water absorption into the stratum corneum occurs as a function of stratum corneum natural moisturizing factor, which consists of a variety of molecules that promote water absorption, including amino acids derived from the proteolysis of epidermal filaggrin, urea, lactate and electrolytes [12,13]. The stratum corneum also prevents epidermal water loss through the presence of an extracellular lipid barrier composed of ceramides, cholesterol, and free fatty acids.

Defects that affect filaggrin, epidermal lipids, or other key components of the stratum corneum can result in the creation of an inadequate epidermal barrier, leading to decreased water content in the epidermis. Increased rates of transepidermal water loss (TEWL) have been detected in skin of patients with atopic dermatitis [10,14], and an association between this finding and mutations in the gene for filaggrin have been reported [15]. In addition, decreased levels of ceramides in the stratum corneum due to upregulation of sphingomyelin deacylase may contribute to increased TEWL in atopic dermatitis [11].

Abnormalities in the skin barrier that result in increased water loss likely contribute to the clinical findings in atopic dermatitis. Higher levels of transepidermal water loss in patients with atopic dermatitis have been associated with greater disease severity [14,16]. In patients with atopic dermatitis, dry skin (xerosis) secondary to decreased epidermal water content may contribute to pruritus and scratching. Resultant cutaneous trauma from scratching can promote the release of proinflammatory mediators and inflammation, thereby worsening pruritus [17]. This itch-scratch cycle may play a role in the persistence of symptoms.

Filaggrin Filaggrin is encoded by the (FLG) gene on the 1q21 epidermal differentiation complex. Filaggrin is a protein that is produced by differentiating keratinocytes that functions to aggregate keratin filaments into a cytoskeleton that, in combination with other components, comprise the cornified cell envelope [11]. Mutations of filaggrin have been demonstrated to cause ichthyosis vulgaris, the most common inherited disorder of keratinization. Ichthyosis vulgaris is characterized by many of the features that are included in the diagnostic criteria for atopic dermatitis including dry skin, keratosis pilaris, and palmar hyperlinearity [18] (See 'Diagnosis' below.) and is frequently associated with atopic dermatitis.

Two well characterized loss of function FLG mutations (R501X and 2282del4) have been shown to be responsible for moderate-severe ichthyosis vulgaris in those who carry two mutant alleles and mild disease in those with only one copy of the allele. One study examined the occurrence of atopic dermatitis in individuals with known mutations of the FLG (R501X and 2282del4) and ichthyosis vulgaris. Atopic dermatitis was found in higher frequency in those who had two mutated FLG alleles compared with those with one, and atopic dermatitis was completely absent in family members who had no copies of the mutated FLG [19]. A number of independent studies in Ireland, Scotland, Denmark, and Japan corroborate these results [19-25]. Many authorities now cite filaggrin defects as a major contributor to the development of atopic dermatitis [2-4].

Spink 5 Spink 5 is a serine protease inhibitor (Kazal-type 5 serine protease inhibitor) that is deficient in Netherton's syndrome (a rare autosomal recessive disorder characterized by severe atopic dermatitis). Spink 5 inhibits a well characterized protease stratum corneum chymotryptic enzyme (SCCE) that is involved in cleaving the intercellular attachments between corneocytes in normal desquamation process. Decreased Spink 5 results in upregulated SCCE function and increased cleavage of intercellular attachments and reduced corneocyte cohesion and compromised barrier function [11].

Epicutaneous sensitization Immune responses to allergens, irritants, and microbes that enter the skin through a defective skin barrier may contribute to the development of local inflammatory responses and the cutaneous findings of atopic dermatitis. Antigen presenting cells in the skin, in particular IgE bearing Langerhans cells, can interact with environmental allergens, leading to the local Th2-mediated inflammatory responses that have been detected in the skin of patients with atopic dermatitis [26].

Immune hypersensitivity Another theory explaining the pathogenesis of atopic dermatitis proposes that the immune system is responsible for atopic disorders [27]. Atopic dermatitis in this view may represent a cutaneous sign of a systemic disorder that is characterized by food allergy, asthma, and allergic rhinitis [1].

The discovery that defects in the filaggrin protein lead to a dysfunctional epidermal barrier and are the primary cause of atopic dermatitis has made this theory less plausible. Emphasis is now placed on the study of the epidermal barrier dysfunction as it relates to the abnormal epidermal architecture and how the immune system responds to the barrier failure [28].

Serum IgE levels vary among patients with atopic dermatitis. Patients with mild to moderate atopic dermatitis typically have much lower (or normal) serum IgE levels compared to patients with severe

atopic dermatitis [11,29]. This finding suggests that the systemic Th2 driven axis of the immune system detected in atopic dermatitis may be related to epidermal barrier dysfunction and the introduction of environmental antigens, rather than intrinsic immune hypersensitivity.

Genetics Most experts believe that atopic dermatitis has a genetic basis. A genetic basis is suggested by twin studies that have found concordance rates of 80 percent for monozygotic twins compared to 20 percent for dizygotic twins [21,30,31].

Other genes In addition to filaggrin, many other genes have been proposed as potential contributors to atopic dermatitis, including genes involved in the creation of the skin barrier or immune regulation [32,33]. Linkage on chromosomes 3q21, 1q21, 17q25, and 20p, all of which correspond closely with known psoriasis loci, have been reported [34,35]. (See 'Filaggrin' above.)

In 2009, the first genome-wide association study of atopic dermatitis detected a strong association between atopic dermatitis and an allele on chromosome 11q13.5 [36]. The risk of atopic dermatitis was approximately 1.5 times greater in patients who were homozygous for the risk allele than in noncarriers (OR 1.47, 95% CI 1.29-1.68). The results of this genome-wide association study were supported by a subsequent case-control study of 511 children with atopic dermatitis and 1000 controls [37]. The casecontrol study implicated the same susceptibility locus as a potential contributor to atopic dermatitis, and found that the effect of the risk allele was independent of and supplementary to filaggrin mutations. Additional studies are necessary to determine how these findings apply to the pathogenesis of atopic dermatitis [37].

Staphylococcus aureus Staphylococcus aureus colonization is common in patients with atopic dermatitis and may play a role in the development of this disorder. (See "Treatment of atopic dermatitis (eczema)", section on 'Staphylococcus aureus'.)

CLINICAL MANIFESTATIONS Atopic dermatitis occurs in the first year of life in 60 percent of cases, and by the age of 5 years in nearly 85 percent of cases. Atopic dermatitis will clear in nearly 40 percent of patients by adulthood [38-40]. There are three age-group stages of atopic dermatitis: infantile (from infancy to 2 years old), childhood (from 2 years old to 12 years old) and the adult stage for those older than 12 years [38]. Virtually all patients report dry skin [39-41]. Pruritus is characteristic, and secondary changes in the skin due to chronic rubbing or scratching are frequently present.

The infantile stage may present with pruritic, red, scaly, and crusted lesions on the extensor surfaces and cheeks or scalp (picture 1A-C). There is usually sparing of the diaper area (picture 2) [38]. Acute lesions can include vesicles and there can be serous exudates and crusting in severe cases.

The childhood stage is characterized by less exudation and often demonstrates lichenified plaques in a flexural distribution, especially of the antecubital and popliteal fossae, volar aspect of the wrists, ankles, and neck (picture 3A-D) [38].

The adult stage of atopic dermatitis is considerably more localized and lichenified and has a similar distribution to the childhood stage, or may be primarily located on the hands and feet [38]. Adult atopic dermatitis is characterized by thickened skin, increased skin markings (lichenification), and excoriated and fibrotic papules (picture 4). In adults, the flexural areas (neck, antecubital fossae, and popliteal fossae) are most commonly involved (picture 5); other common sites include the face, wrists, and forearms.

In severe cases, any area of the body can be involved, although it is uncommon to see lesions in the axillary, gluteal, or groin area; lesions in these locations should prompt consideration of other diagnoses such as psoriasis. The presence of pustules within areas of dermatitis suggests secondary infection with Staphylococcus aureus.

DIAGNOSIS Atopic dermatitis is diagnosed by observing its representative clinical features. The United Kingdom working group on atopic dermatitis published criteria for diagnosing atopic dermatitis that include the following [39]:

Evidence of pruritic skin, including the report by a parent of a child rubbing or scratching.

In addition to itchy skin, three or more of the following are needed to make the diagnosis:

History of skin creases being involved. These include: antecubital fossae, popliteal fossae, neck, areas around eyes, fronts of ankles.The presence of generally dry skin within the past year.Symptoms beginning in a child before the age of two years. This criterion is not used to make the diagnosis in a child who is under four years old.Visible evidence of dermatitis involving flexural surfaces. For children

under four years old, this criterion is met by dermatitis affecting the cheeks or forehead and outer aspects of the extremities.

The UK working group's analysis excluded allergy criteria as originally proposed by Hanifin and Rajka. The UK working group data have been validated by investigators from the Netherlands [41].

Laboratory testing, including IgE levels, are not used routinely in the evaluation of patients with suspected atopic dermatitis, and are not currently recommended.

When the diagnosis is uncertain, we suggest that patients be referred to a specialist (eg, dermatologist, allergist).

DIFFERENTIAL DIAGNOSIS The differential diagnosis of atopic dermatitis includes other eczematous disorders such as contact dermatitis (picture 6), seborrheic dermatitis (picture 7), and drug reactions (picture 8). (See "Overview of dermatitis".)

In infants, considerations include psoriasis (picture 9), scabies (picture 10), Wiskott-Aldrich syndrome, hyperimmunoglobulin E syndrome (picture 11), nutritional deficiencies, acrodermatitis enteropathica (picture 12) and Netherton's syndrome. (See "Epidemiology, pathophysiology, clinical manifestations, and diagnosis of psoriasis" and "Scabies" and "Wiskott-Aldrich syndrome" and "Hyperimmunoglobulin E syndrome" and "Zinc deficiency and supplementation in children and adolescents".)

INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. (See "Patient information: Atopic dermatitis (eczema)".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, http://www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS Atopic dermatitis is a chronic inflammatory skin condition that appears to involve genetic defects in the proteins and lipids supporting the epidermal barrier. Disruption of the barrier results in inflammation of the skin. (See 'Introduction' above.)

The diagnosis of atopic dermatitis is generally based on its typical clinical presentation (see 'Clinical manifestations' above):

Most patients have manifestations of atopic dermatitis by age five to seven years.In children, acute skin lesions that appear as intensely pruritic erythematous patches with papules and some crusting can be seen on the face, scalp, extremities, or trunk; diaper areas are usually spared.The skin lesions in older individuals with more chronic disease are characterized by thickened skin, increased skin markings (lichenification), and excoriated and fibrotic papules. In adults, the flexural areas (neck, antecubital fossae, and popliteal fossae) are most commonly involved.We suggest not performing routine laboratory testing in patients felt clinically to have atopic dermatitis. When the diagnosis is uncertain, we suggest that patients be referred to a specialist (eg, dermatologist, allergist). (See 'Diagnosis' above.)The differential diagnosis of atopic dermatitis includes other eczematous disorders such as contact dermatitis, seborrheic dermatitis, and drug reactions. (See 'Differential diagnosis' above.)

Use of UpToDate is subject to the Subscription and License Agreement REFERENCES 1. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol 2003; 112:S118. 2. Sandilands A, Smith FJ, Irvine AD, McLean WH. Filaggrin's fuller figure: a glimpse into the genetic architecture of atopic dermatitis. J Invest Dermatol 2007; 127:1282. 3. Chan LS. Atopic dermatitis in 2008. Curr Dir Autoimmun 2008; 10:76. 4. McGrath JA, Uitto J. The filaggrin story: novel insights into skin-barrier function and disease. Trends Mol Med 2008; 14:20. 5. Williams H, Robertson C, Stewart A, et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol 1999; 103:125. 6. Shaw TE, Currie GP, Koudelka CW, Simpson EL. Eczema prevalence in the United States: data from the 2003 National Survey of Children's Health. J Invest Dermatol 2011; 131:67. 7. Trepka MJ, Heinrich J, Wichmann HE. The epidemiology of atopic diseases in Germany: an east-west comparison. Rev Environ Health 1996; 11:119. 8. Kang, K, Polster, AM, Nedorost, ST, et al. Atopic dermatitis. In: Dermatology, Bolognia, JL, Jorizzo, JL, Rapini, RP, et al (Eds), Mosby, New York 2003. p.199.

9. Elias PM, Steinhoff M. "Outside-to-inside" (and now back to "outside") pathogenic mechanisms in atopic dermatitis. J Invest Dermatol 2008; 128:1067. 10. Grimalt R, Mengeaud V, Cambazard F, Study Investigators' Group. The steroid-sparing effect of an emollient therapy in infants with atopic dermatitis: a randomized controlled study. Dermatology 2007; 214:61. 11. Cork MJ, Robinson DA, Vasilopoulos Y, et al. New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions. J Allergy Clin Immunol 2006; 118:3. 12. Verdier-Svrain S, Bont F. Skin hydration: a review on its molecular mechanisms. J Cosmet Dermatol 2007; 6:75. 13. Rawlings AV, Harding CR. Moisturization and skin barrier function. Dermatol Ther 2004; 17 Suppl 1:43. 14. Flohr C, England K, Radulovic S, et al. Filaggrin loss-of-function mutations are associated with earlyonset eczema, eczema severity and transepidermal water loss at 3 months of age. Br J Dermatol 2010; 163:1333. 15. Nemoto-Hasebe I, Akiyama M, Nomura T, et al. Clinical severity correlates with impaired barrier in filaggrin-related eczema. J Invest Dermatol 2009; 129:682. 16. Gupta J, Grube E, Ericksen MB, et al. Intrinsically defective skin barrier function in children with atopic dermatitis correlates with disease severity. J Allergy Clin Immunol 2008; 121:725. 17. Lodn M. The skin barrier and use of moisturizers in atopic dermatitis. Clin Dermatol 2003; 21:145. 18. Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 2006; 38:337. 19. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006; 38:441. 20. Sandilands A, O'Regan GM, Liao H, et al. Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis. J Invest Dermatol 2006; 126:1770. 21. Weidinger S, Illig T, Baurecht H, et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006; 118:214. 22. Nomura T, Sandilands A, Akiyama M, et al. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol 2007; 119:434. 23. Nomura T, Akiyama M, Sandilands A, et al. Specific filaggrin mutations cause ichthyosis vulgaris and are significantly associated with atopic dermatitis in Japan. J Invest Dermatol 2008; 128:1436.

24. Rogers AJ, Celedn JC, Lasky-Su JA, et al. Filaggrin mutations confer susceptibility to atopic dermatitis but not to asthma. J Allergy Clin Immunol 2007; 120:1332. 25. Baurecht H, Irvine AD, Novak N, et al. Toward a major risk factor for atopic eczema: meta-analysis of filaggrin polymorphism data. J Allergy Clin Immunol 2007; 120:1406. 26. Leung DY. Atopic dermatitis: new insights and opportunities for therapeutic intervention. J Allergy Clin Immunol 2000; 105:860. 27. Boguniewicz M. Atopic dermatitis: beyond the itch that rashes. Immunol Allergy Clin North Am 2005; 25:333. 28. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol 2009; 9:437. 29. Flohr C, Johansson SG, Wahlgren CF, Williams H. How atopic is atopic dermatitis? J Allergy Clin Immunol 2004; 114:150. 30. Larsen FS, Holm NV, Henningsen K. Atopic dermatitis. A genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol 1986; 15:487. 31. Schultz Larsen F. Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol 1993; 28:719. 32. Guttman-Yassky E, Surez-Farias M, Chiricozzi A, et al. Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis. J Allergy Clin Immunol 2009; 124:1235. 33. Barnes KC. An update on the genetics of atopic dermatitis: scratching the surface in 2009. J Allergy Clin Immunol 2010; 125:16. 34. Lee YA, Wahn U, Kehrt R, et al. A major susceptibility locus for atopic dermatitis maps to chromosome 3q21. Nat Genet 2000; 26:470. 35. Cookson WO, Ubhi B, Lawrence R, et al. Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat Genet 2001; 27:372. 36. Esparza-Gordillo J, Weidinger S, Flster-Holst R, et al. A common variant on chromosome 11q13 is associated with atopic dermatitis. Nat Genet 2009; 41:596. 37. O'Regan GM, Campbell LE, Cordell HJ, et al. Chromosome 11q13.5 variant associated with childhood eczema: an effect supplementary to filaggrin mutations. J Allergy Clin Immunol 2010; 125:170. 38. Rudikoff D, Lebwohl M. Atopic dermatitis. Lancet 1998; 351:1715. 39. Williams HC. Clinical practice. Atopic dermatitis. N Engl J Med 2005; 352:2314.

40. Williams HC, Strachan DP. The natural history of childhood eczema: observations from the British 1958 birth cohort study. Br J Dermatol 1998; 139:834. 41. Brenninkmeijer EE, Schram ME, Leeflang MM, et al. Diagnostic criteria for atopic dermatitis: a systematic review. Br J Dermatol 2008; 158:754.

2011 UpToDate, Inc. All rights reserved. | Subscription and License Agreement Licensed to: k g

A newer version of UpToDate is now available, and the information in this version may no longer be current.Treatment of atopic dermatitis (eczema)

Authors William L Weston, MD William Howe, MD Section Editors Robert P Dellavalle, MD, PhD, MSPH Moise L Levy, MD Deputy Editor Rosamaria Corona, DSc, MD

Last literature review version 19.1: January 2011 | This topic last updated: October 1, 2010 (More)

INTRODUCTION Atopic dermatitis (AD) is a chronic inflammatory skin condition that appears to involve a genetic defect in the proteins supporting the epidermal barrier. Atopy, referring to "out of place", describes a group of disorders that include eczema, asthma, and allergic rhinitis [1]. However, such a link between AD and asthma and hay fever has been called into question and is now controversial [2-6]. (See "Risk factors for asthma", section on 'Atopy' and "Role of allergy in atopic dermatitis (eczema)".)

The terms "dermatitis" and "eczema" are frequently used interchangeably. When the term "eczema" is used alone, it usually refers to atopic dermatitis (atopic eczema). "Eczematous" also connotes some scaling, crusting, or serous oozing as opposed to mere erythema.

Conventional therapy for atopic dermatitis is reviewed here. The management of severe, refractory atopic dermatitis and the epidemiology, pathogenesis, clinical manifestations, and diagnosis of atopic dermatitis are discussed separately. (See "Management of severe refractory atopic dermatitis (eczema)" and "Epidemiology, clinical manifestations, and diagnosis of atopic dermatitis (eczema)".)

GENERAL APPROACH Advances in the therapy of atopic dermatitis have focused on epidermal barrier repair as genetic studies have demonstrated epidermal filaggrin mutations as a likely cause of AD [24,7]. Epidermal filaggrin mutations result in dry and sensitive skin. Currently, standard modalities will continue to be important in the long-term management of these patients, centering around the use of topical antiinflammatory preparations and lubrication of the skin [8,9]. Most cases of atopic dermatitis are chronic. Thus, the goal of therapy is to improve symptoms while minimizing exposure to potentially toxic drugs.

One systematic review of randomized, controlled trials of therapies for atopic dermatitis found that there was reasonable evidence from these studies to support the use of topical corticosteroids, oral cyclosporine, ultraviolet light therapy, and some psychological approaches [10]. For other modalities there was either insufficient or absent evidence to support their use. Subsequent to that review, there have been a number of randomized trials published demonstrating the effectiveness of topical calcineurin inhibitors. While the absence of evidence does not imply absence of efficacy, there is a need for well designed studies in the therapy of atopic dermatitis.

The general approach to treatment involves the elimination of exacerbating factors, restoring the skin's abnormal barrier function, and hydrating the skin. We recommend the use of emollients in patients with noninflamed skin, and the use of either topical corticosteroids or topical calcineurin inhibitors in patients with inflamed skin.

ELIMINATION OF EXACERBATING FACTORS Exacerbating factors in atopic dermatitis that disrupt an abnormal epidermal barrier include excessive bathing, low humidity environments, emotional stress, xerosis (dry skin), overheating of skin, and exposure to solvents and detergents [11,12]. Avoiding these situations is helpful for acute flares as well as for long-term management.

Adjunctive measures that can be helpful in all patients with dermatitis include [13]:

Avoid trigger factors such as heat, perspiration, low humidityTreat skin infections such as staphylococcus aureus and herpes simplex (see 'Management of infection' below).Use antihistamines for sedation and control of itching (see 'Controlling pruritus' below)Treat stress and anxiety

There is controversy regarding whether environmental or food allergies are an exacerbating factor in a small subset of patients with atopic dermatitis. (See "Role of allergy in atopic dermatitis (eczema)".)

MAINTAINING SKIN HYDRATION Evaporation of water on the skin leads to xerosis in patients with atopic dermatitis; skin hydration is a key component of their overall management. Lotions, which have a high water and low oil content, can worsen xerosis via evaporation and trigger a flare of the disease. In contrast, thick creams (eg, Eucerin, Cetaphil, Nutraderm), which have a low water content, or ointments (eg, petroleum jelly, Aquaphor, Petrolatum), which have zero water content, better protect against xerosis.

A randomized trial in infants with AD who required moderate or high potency topical steroids found that infants treated with emollients had significantly decreased requirements for topical steroids compared with a control group of infants who were not treated with emollients [14]. Emollients are best applied immediately after bathing when the skin is well hydrated.

Some controversy exists concerning whether showering or bathing is preferable in patients with atopic dermatitis. Most authorities recommend a hydrating bath followed by immediate emollient application,

but others recommend a shower of short duration. Emollients are the key to restoring the defective epidermal barrier. No well designed studies have been published to address this controversy. We feel that either option is reasonable but suggest bathing to most patients; whether bath or shower, rapid application of emollients or prescribed topical preparations is important.

CONTROLLING PRURITUS Antihistamines are widely used as a therapeutic adjunct in patients with atopic dermatitis to treat both pruritus and eye irritation [15]. The evidence supporting their use is relatively weak since no large, randomized, placebo-controlled trials with definitive conclusions have been performed [16]. Nevertheless, the sedating antihistamines appear to be most effective (eg, diphenhydramine, hydroxyzine, and cyproheptadine), although nonsedating preparations such as fexofenadine or loratadine may also be useful. Higher than normal doses may be necessary.

Doxepin, a tricyclic antidepressant with potent H1 and H2 blocking properties, is valuable as a secondline antihistamine if others fail. Tepid baths to hydrate and cool the skin can also temporarily relieve itching.

Wet dressings (wet wraps) help sooth the skin, reduce pruritus, reduce redness, debride crusts, and limit access to the skin. Emollients are applied to the skin, and dampened cotton garments are worn over the affected area and covered with a dry garment [17]. The patient may use these dressings overnight or change them every eight hours during the day.

THERAPIES FOR INFLAMMATION

Corticosteroids Topically applied corticosteroids are the mainstay of therapy for AD. A low potency corticosteroid cream or ointment (eg, 1 or 2.5% hydrocortisone) is effective for patients with mild atopic dermatitis (table 1A-B). A medium potency corticosteroid ointment (eg, fluocinolone 0.025% or triamcinolone 0.1%) may be needed for those with more severe disease. Higher potency topical corticosteroids can be used for up to 10 days in some patients with acute flares, and then replaced with lower potency preparations until the lesions resolve.

Topical corticosteroids can be used one or more times daily, although no clear benefit has been demonstrated with more than once daily application [18-21]. Additional emollients may not be required if the corticosteroid is prescribed in an ointment base.

Potent steroids (class I-IV) (table 1A-B) are generally avoided in skin folds and on the face; however, limited brief use of potent steroids may produce a rapid response after which patients can be switched to lower potency preparations. In general, the use of potent steroids in these areas should be limited to care prescribed by a dermatologist.

Maintenance therapy that includes intermittent use of a topical corticosteroid may help prevent relapse [22,23]. A randomized trial of twice weekly fluticasone propionate (0.05% cream or 0.005% ointment) in addition to daily emollients in patients with moderate to severe atopic dermatitis who had brought a flare under control with fluticasone found a significantly lower rate of relapse over 16 weeks in the fluticasone cream and ointment groups than in the placebo cream and ointment groups (19 versus 64 percent and 40 versus 56 percent, respectively) [22].

An acute exacerbation of chronic atopic dermatitis can sometimes be aborted by a short course of systemic glucocorticoids (eg, prednisone 40 to 60 mg/day for three to four days, then 20 to 30 mg/day for three to four days). Systemic glucocorticoids also are effective for patients with severe chronic disease, but are best avoided because of the need for long-term use and the associated side effects in a disease that is not life-threatening. (See "Major side effects of systemic glucocorticoids".)

Topical calcineurin inhibitors The topical calcineurin inhibitors appear to be effective for the treatment of atopic dermatitis [24], and, unlike topical corticosteroids, do not cause skin atrophy. For this reason they may be particularly useful on the face, neck, and in skin folds. Both topical preparations are approved by the United States Food and Drug Administration (FDA) for use in children over the age of two. However, concerns have been raised by the FDA about a possible link to cancers.

Tacrolimus and pimecrolimus are applied twice a day. Tacrolimus comes in two strengths; the 0.1% formulation is appropriate initial therapy for adults, and the 0.03% formulation is appropriate for children and for adults who do not tolerate the higher dose. In patients who do not tolerate tacrolimus because of burning or stinging, pimecrolimus may be better tolerated.

Efficacy and minor side effects Topical calcineurin inhibitors are generally recognized as being equal in strength to low potency (Class IV) topical steroids (table 1A-B), and should be considered a secondline therapy [25].

Topical tacrolimus is an effective second-line alternative to topical corticosteroids [26-30]. In addition to its inhibitory effect on cytokine production, topical tacrolimus causes alterations in epidermal antigenpresenting dendritic cells that may result in decreased immunologic response to antigens [31]. The efficacy of tacrolimus has been demonstrated in several randomized, controlled trials [26,32-34]. Unlike topical corticosteroids, tacrolimus ointment does not cause skin atrophy, which may provide an advantage for patients with facial disease. Tacrolimus has been used successfully in patients with refractory eyelid disease [35]. Transient burning, erythema, and pruritus are the most common adverse effects [32]. Pimecrolimus 1% cream is a calcineurin inhibitor like tacrolimus that was developed specifically to treat inflammatory skin conditions. Its mechanism of action is similar to topical tacrolimus, and it does not appear to have systemic immune effects [36]. A pooled analysis of two independent, sixweek trials that included 403 children with predominantly moderate atopic dermatitis found significant benefits with pimecrolimus therapy compared with vehicle treatment [37]. A randomized trial of early treatment with pimecrolimus in 713 children found that pimecrolimus was effective in preventing flares of atopic dermatitis and reduced the need for topical steroids; benefits persisted after one year of use [38]. Another randomized trial of 543 adults with atopic dermatitis also found that pimecrolimus 1% cream applied twice daily at the first sign of disease activity significantly reduced the number of flares over a 26 week period [39].

Comparison studies Tacrolimus ointment, particularly the 0.1% preparation, may be somewhat more effective than pimecrolimus cream, although it may also cause somewhat greater local irritation. Examples of studies supporting this concept include:

A six-week randomized trial sponsored by the manufacturer of pimecrolimus that compared twice daily treatment with pimecrolimus 1% cream with tacrolimus 0.03% ointment in 141 children (ages 2 to 17) with moderate atopic dermatitis concluded that pimecrolimus had better local tolerability [40]. Although the authors reported no difference in efficacy between the treatments, after six weeks there appeared to be a trend toward more children having almost or completely cleared atopic dermatitis when treated with tacrolimus (42 versus 30 percent, p = 0.12).A report of three six-week randomized trials sponsored by the manufacturer of tacrolimus found similar results [41]. The trials, which enrolled a total of 1065 patients, compared twice daily treatment with pimecrolimus 1% cream with tacrolimus ointment (0.3% in 426 children with mild atopic dermatitis; 0.1% in 226 children with moderate to severe atopic dermatitis and in 413 adults with mild to very severe atopic dermatitis). In a combined analysis, significantly more patients treated with tacrolimus had almost or completely cleared atopic dermatitis (43 versus 31 percent). More adults treated with tacrolimus noted burning at the application site, typically early in the course of therapy. In pediatric patients with mild disease (who were treated with the lower concentration of tacrolimus used in the study above), there was a nonsignificant trend toward greater clearing with tacrolimus (57 versus 50 percent).

Systematic reviews of randomized trials have suggested that topical calcineurin inhibitors and low potency topical steroids have similar efficacy when used to treat moderate to severe atopic dermatitis [24,25]. In a subsequent randomized, non-inferiority trial of children with moderate to severe atopic dermatitis who had failed to improve sufficiently with topical corticosteroids, tacrolimus 0.03% ointment applied twice daily for three weeks was as effective as fluticasone 0.005% ointment (a high potency topical corticosteroid) [42]. Of note, 60 percent of the patients in this study had previously been treated with a high potency or superpotent topical corticosteroid, a factor that may have induced bias favoring tacrolimus.

Safety Although in controlled trials the topical calcineurin inhibitors have appeared to be safe in adults and children [26,32,33,43,44], in 2005, based upon case reports, animal studies, and the known risks with systemic calcineurin inhibitors, the FDA issued warnings about a possible link between the topical calcineurin inhibitors and cancer [45], and in 2006 placed a "black box" warning on the prescribing information for these medications [46].

Issues of concern include:

Animal studies in mice, rats, and monkeys have found an increased risk of lymphoma and skin cancers with topical or oral exposure to calcineurin inhibitorsAs of December 2004, the FDA had received 29 reports of cancers in adults and children treated with topical calcineurin inhibitors; approximately half the cases were lymphomas and the other half were cutaneous tumors

However, no definite causal relationship has been established [47], and two case-control studies did not detect an increased risk of lymphoma among patients treated with topical calcineurin inhibitors [48,49]. While further study is underway, the FDA has made the following recommendations:

Use these agents only as second-line therapy in patients unresponsive to or intolerant of other treatmentsAvoid the use of these agents in children younger than two years of age; clinical studies have found higher rates of upper respiratory infections in children younger than two who were treated with pimecrolimusUse these agents only for short periods of time and use the minimum amount necessary to control symptoms; avoid continuous useAvoid the use of these agents in patients with compromised immune systems

In the absence of better data, these seem like reasonable precautions. However, providers and patients will need to weigh the risks and benefits in comparison to those of other therapies. In particular, calcineurin inhibitors may continue to have an important role in the management of atopic dermatitis in areas at high risk for skin atrophy when treated with corticosteroids (eg, face) [50].

OTHER THERAPIES The management of severe atopic dermatitis that is resistant to conventional therapy is a challenge and frequently requires the help of a dermatologist. A number of alternatives are available:

Ultraviolet light therapy (phototherapy) with PUVA (psoralens plus ultraviolet A radiation), broadband UVA, broadband UVB, combined UVA and UVB, narrow-band UVB, or UVA1 is successful in controlling atopic dermatitis [51-53]. Some studies suggest that either narrowband UVB or UVA-1 may be more effective than treatment with combined UVA and UVB, broadband UVA, or broadband UVB [51,52,5456]. However, phototherapy is expensive ($25 to $100 per treatment) and may lead to an increased risk of melanoma and nonmelanoma skin cancer [57-59]. Thus, treatment with this modality is limited to severe cases.Oral calcineurin inhibitors can be used to treat atopic dermatitis. Oral cyclosporine, in doses of 3 to 6 mg/kg per day, is effective for severe atopic dermatitis [60]. In one study that used a body weight-independent dosing of cyclosporine microemulsion, 150 mg/day was effective when compared to 300 mg/day in the short term treatment of atopic dermatitis, and was associated with better renal tolerance [61]. Short courses of cyclosporine 5 mg/kg per day (multiple courses of 12 weeks) also have been successful in children with atopic dermatitis [62]. Monitoring of patients receiving cyclosporine includes measuring blood pressure and serum creatinine every two weeks for three months, followed by monthly monitoring. Significant elevations of either are an indication to lower the dose or stop treatment. Oral tacrolimus or pimecrolimus also may be used in some cases, with similar concerns regarding side effects [63]. (See "Pharmacology and side effects of cyclosporine and tacrolimus".) Topical cyclosporine does not appear to be effective [64].Occasionally immunosuppressants such as methotrexate, azathioprine [65], or mycophenolate mofetil may be used. These therapies should be prescribed by a dermatologist and are generally avoided in children.Patients with pustules should be evaluated with bacterial cultures and treated with appropriate oral antibiotics.Topical preparations containing cromolyn sodium may provide some benefit [66].

Probiotic therapy with Lactobacillus and other organisms has been studied for the treatment of atopic dermatitis in infants [67], but is probably not of significant benefit [68-70]. Oral essential fatty acid supplementation also does not appear to be beneficial [71]. The use of Chinese herbal medications for atopic dermatitis has not been adequately evaluated in clinical trials [72].

There have been case reports and small uncontrolled studies showing improvement in refractory cases with the anti-IgE monoclonal antibody omalizumab [73], the anti-CD11A monoclonal antibody efalizumab [74,75], and the anti-CD20 monoclonal antibody rituximab [76]. However, due to an increased risk of progressive multifocal leukoencephalopathy observed in patients taking efalizumab, this drug was withdrawn from the United States market on June 8, 2009 [77], and is also being withdrawn from other markets internationally.

MANAGEMENT OF INFECTION Patients with atopic dermatitis are at increased risk for cutaneous bacterial, viral, and fungal infections.

Staphylococcus aureus Staphylococcus aureus is a frequent skin colonizer in patients with atopic dermatitis. The organism can be isolated from the skin lesions of 76 to 100 percent of patients [78]. S. aureus is isolated from the skin of only 2 to 25 percent of unaffected individuals [78]. The increased rates of colonization in patients with atopic dermatitis may be secondary to the impaired epidermal barrier and reduction of cutaneous antimicrobial peptides (cathelicidins and beta-defensins) [78,79].

The presence of S. aureus colonization may influence the development of atopic dermatitis in young children. A prospective cohort study (n=1079) evaluated the association between nasal colonization with S. aureus and atopic dermatitis in children under the age of two [80]. The presence and severity of atopic dermatitis was assessed via parent questionnaires. Children with positive nasal cultures at the age of six months exhibited a higher prevalence of symptoms of atopic dermatitis during the first and second years of life than those with negative cultures (adjusted OR 1.67, 95% CI 1.15-2.44 and 1.86, 95% CI 1.28-2.69, respectively). S. aureus colonization also had an effect on disease severity. In the second year of life, children who had positive nasal cultures at age 6 months possessed a higher risk for moderate to severe atopic dermatitis (adjusted OR 3.27, 95% CI 1.30-8.03) than for mild disease (adjusted OR 1.57, 95% CI 1.04-2.37). The findings of this survey-based study are not sufficient to implicate S. aureus as a major causative factor of atopic dermatitis; further studies are necessary to determine the role of S. aureus in the development of the clinical features of this disease.

Methicillin-resistant S. aureus (MRSA) infections have increased in the general population, and can occur in patients with atopic dermatitis [78,81]. A minority (13 to 18 percent) of atopic dermatitis patients are colonized with MRSA [82,83].

Management of clinical infection Treatment of patients with clinically infected skin is recommended. Signs of infection include honey-colored crusting, folliculitis, and pyoderma (picture 1A-B) [17]. Topical

mupirocin is effective for patients with localized infections, but oral antibiotic therapy with cephalosporins or penicillinase-resistant penicillins are typically used for more extensive infections [84].

We recommend culturing infected skin prior to treatment. If MRSA is present, therapy with an appropriate antibiotic is indicated. (See "Evaluation and management of suspected methicillin-resistant Staphylococcus aureus skin and soft tissue infections in children", section on 'Antimicrobial therapy' and "Treatment of skin and soft tissue infections due to methicillin-resistant Staphylococcus aureus in adults", section on 'Oral therapy'.)

Bleach baths Sodium hypochlorite 6% solution (liquid chlorine bleach) has activity against S. aureus including MRSA. Dilute bleach baths have been used to decrease the frequency of skin infections in patients with atopic dermatitis, although studies of the effectiveness of this intervention are limited [84,85]. Patients are instructed to add one quarter to one half cup of bleach to a full tub (40 gallons) of lukewarm water, then soak in the bath for 5 to 10 minutes [17]. Afterwards, patients rinse with fresh water, pat themselves dry, and immediately apply an emollient and/or prescribed medications. The baths are taken two times per week.

Antimicrobials in the absence of infection S. aureus colonization may be an exacerbating factor for atopic dermatitis [17]. However, studies conflict on whether antimicrobial therapies for S. aureus colonization are effective in reducing the severity of atopic dermatitis.

A systematic review found insufficient evidence to recommend the use of oral antibiotics for the treatment of atopic dermatitis in the absence of clinical infection [86]. The same review found that topical antibiotics or antiseptics reduced colonization with S. aureus in patients with atopic dermatitis, but could not conclude that treatment with these agents in combination with topical corticosteroids induced greater clinical improvement than topical corticosteroids alone. However, the systematic review primarily was based on poor quality studies, and cannot definitively discount antimicrobial therapies for patients without overt infection.

A more recent three month randomized trial (n = 31) of children with atopic dermatitis investigated the effect of antimicrobial therapy on disease severity and found evidence of effectiveness for a combination of mupirocin and bleach baths [78]. Patients had acute signs of infection at the start of the trial, but were followed for a total of three months to evaluate the efficacy of bleach baths and mupirocin ointment on disease severity. All patients received oral cephalexin (50 mg/kg/day for 14

days), but were randomly assigned to receive intranasal mupirocin ointment for five consecutive days per month plus twice weekly bleach baths or intranasal petrolatum and plain water baths.

Mean reductions in the Eczema Area and Severity Index (EASI) scores were greater for the treatment group (-10.4 2.8 after one month and -15.3 3.8 after three months) versus the control group (-2.5 1.6 after one month and -3.2 1.6 after three months). The study also assessed EASI scores for areas that were not immersed in the bleach baths (head and neck) versus scores for the rest of the body. In contrast to the submerged body sites, significant reductions in EASI scores were not observed on the head and neck.

Viral infections Atopic dermatitis patients with lesions that are infected with herpes simplex (called eczema herpeticum or Kaposi's varicelliform eruption) should be treated immediately with oral antiviral therapy. Examination reveals skin with punched-out erosions, hemorrhagic crusts, and/or vesicles (picture 2A-C). Involved skin may be pruritic or painful, and lesions may be widespread. The diagnosis should be considered in patients who fail to respond to oral antibiotics [84]. Cases of life-threatening dissemination have been reported, and intravenous antiviral therapy may be necessary in severe cases [84]. (See "Treatment of herpes simplex virus type 1 infection in immunocompetent patients".)

Patients with atopic dermatitis may also develop widespread molluscum contagiosum infections (picture 3). (See "Molluscum contagiosum".)

Fungal infections Dermatophyte infections are more common in patients with atopic dermatitis, and can be treated with standard regimens of topical or oral antifungals. (See "Dermatophyte (tinea) infections".)

In addition, the Malessezia furfur yeast (a normal component of skin flora) may be an exacerbating factor in patients with head/neck atopic dermatitis [87]. Elevated Malassezia-specific IgE levels have been reported in these patients [87]. Treatment may result in improvement. (See "Role of allergy in atopic dermatitis (eczema)", section on 'Malassezia'.)

REFERRAL Many patients with atopic dermatitis can initially be treated by a nonspecialist. We suggest that patients be referred to a specialist (eg, dermatologist, allergist) in the following circumstances:

When the diagnosis is uncertainWhen patients have failed to respond to appropriate therapyIf treatment of atopic dermatitis of the face or skin folds with high potency topical corticosteroids is being contemplatedIf treatment with systemic immunosuppressive agents is being considered

PREGNANCY The treatment of atopic dermatitis in pregnant women is discussed separately. (See "Recognition and management of allergic disease during pregnancy", section on 'Atopic dermatitis'.)

INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. (See "Patient information: Atopic dermatitis (eczema)".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS Atopic dermatitis is a chronic inflammatory skin condition that involves a complex interaction between environmental and genetic factors. When the term "eczema" is used alone, it usually refers to atopic dermatitis (atopic eczema). (See 'Introduction' above.)

The goals of treatment are to reduce symptoms (pruritus and dermatitis), prevent exacerbations, and minimize therapeutic risks.

General measures Adjunctive measures that can be helpful in all patients with dermatitis include (see 'Elimination of exacerbating factors' above):

Avoid trigger factors such as heat, perspiration, low humidityTreat skin infections such as staphylococcus aureus and herpes simplexUse antihistamines for sedation and control of itchingTreat stress and anxiety

A sleeping environment with minimal dust and upholstery reduces exposure to house dust mites and may potentially reduce the severity of atopic dermatitis.

In infants, avoidance of certain foods can be helpful. Common food triggers include eggs, nuts, peanut butter, chocolate, milk, seafoods, and soya.

Noninflamed skin When skin is not inflamed, patients should bathe daily and then immediately apply an emollient. Patients should use the highest oil content emollient that they will accept. (See 'Maintaining skin hydration' above.)

Inflamed skin

We suggest that patients with inflamed skin be initially treated with topical therapy using corticosteroids rather than a calcineurin inhibitor (Grade 2B). Topical corticosteroids can be applied once daily. (See 'Corticosteroids' above.)The face and skin folds are areas that are at high risk for atrophy with corticosteroids. Initial therapy in these areas should start with a low potency steroid (class V or VI) (table 1A-B), such as desonide 0.05% ointment daily for up to three weeks. Potent steroids (class I-IV) are generally avoided in skin folds and on the face; however, limited brief use of potent steroids may produce a rapid response after which patients can be switched to lower potency preparations. In general, the use of potent steroids in these areas should be limited to care prescribed by a dermatologist. (See 'Corticosteroids' above.)We suggest that patients who require therapy to the face or skin folds for more than three weeks be treated with a topical calcineurin inhibitor (ie, tacrolimus or pimecrolimus) rather than a topical steroid (Grade 2B). (See 'Topical calcineurin inhibitors' above.)Tacrolimus and pimecrolimus are applied twice a day. Tacrolimus comes in two strengths; the 0.1% formulation is appropriate initial therapy for adults, and the 0.03% formulation is appropriate for children and for adults who do not tolerate the higher dose. In patients who do not tolerate tacrolimus because of burning or stinging, pimecrolimus may be better tolerated. (See 'Topical calcineurin inhibitors' above.)Tacrolimus and pimecrolimus may be used on any skin surface. However, these agents are expensive, and there have been concerns raised about reports of malignancies in children and adults. (See 'Safety' above.)If patients fail topical treatment, systemic immunosuppressive therapy may be of benefit. Such therapy should generally be prescribed by a specialist and is generally avoided in children. (See 'Other therapies' above.)Patients with refractory disease with recurrent skin infections may need evaluation for immune deficiency. (See "Epidemiology, clinical manifestations, and diagnosis of atopic dermatitis (eczema)", section on 'Differential diagnosis'.)

Infected skin

Staphylococcus aureus infections should be treated with topical or oral antibiotics. When skin infection is suspected, a culture should be obtained to rule out methicillin-resistant S. aureus (MRSA). Although colonization with S. aureus appears to be an exacerbating factor for atopic dermatitis, further studies are necessary to determine whether antimicrobial interventions that reduce S. aureus colonization reduce disease severity.Herpes simplex infections (eczema herpeticum or Kaposi's varicelliform

eruption) in atopic dermatitis can be widespread, and rarely life-threatening. Affected patients should be treated with oral antivirals. Intravenous therapy may be necessary in severe cases.

Use of UpToDate is subject to the Subscription and License Agreement REFERENCES 1. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol 2003; 112:S118. 2. Sandilands A, Smith FJ, Irvine AD, McLean WH. Filaggrin's fuller figure: a glimpse into the genetic architecture of atopic dermatitis. J Invest Dermatol 2007; 127:1282. 3. Chan LS. Atopic dermatitis in 2008. Curr Dir Autoimmun 2008; 10:76. 4. McGrath JA, Uitto J. The filaggrin story: novel insights into skin-barrier function and disease. Trends Mol Med 2008; 14:20. 5. Brenninkmeijer EE, Schram ME, Leeflang MM, et al. Diagnostic criteria for atopic dermatitis: a systematic review. Br J Dermatol 2008; 158:754. 6. Baurecht H, Irvine AD, Novak N, et al. Toward a major risk factor for atopic eczema: meta-analysis of filaggrin polymorphism data. J Allergy Clin Immunol 2007; 120:1406. 7. Rogers AJ, Celedn JC, Lasky-Su JA, et al. Filaggrin mutations confer susceptibility to atopic dermatitis but not to asthma. J Allergy Clin Immunol 2007; 120:1332. 8. Charman C. Clinical evidence: atopic eczema. BMJ 1999; 318:1600. 9. Sudilovsky A, Muir JG, Bocobo FC. A comparison of single and multiple applications of halcinonide cream. Int J Dermatol 1981; 20:609. 10. Hoare C, Li Wan Po A, Williams H. Systematic review of treatments for atopic eczema. Health Technol Assess 2000; 4:1. 11. Langan SM, Williams HC. What causes worsening of eczema? A systematic review. Br J Dermatol 2006; 155:504. 12. Langan SM, Bourke JF, Silcocks P, Williams HC. An exploratory prospective observational study of environmental factors exacerbating atopic eczema in children. Br J Dermatol 2006; 154:979. 13. Ellis C, Luger T, Abeck D, et al. International Consensus Conference on Atopic Dermatitis II (ICCAD II): clinical update and current treatment strategies. Br J Dermatol 2003; 148 Suppl 63:3.

14. Grimalt R, Mengeaud V, Cambazard F, Study Investigators' Group. The steroid-sparing effect of an emollient therapy in infants with atopic dermatitis: a randomized controlled study. Dermatology 2007; 214:61. 15. Nuovo J, Ellsworth AJ, Larson EB. Treatment of atopic dermatitis with antihistamines: lessons from a single-patient, randomized clinical trial. J Am Board Fam Pract 1992; 5:137. 16. Klein PA, Clark RA. An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch Dermatol 1999; 135:1522. 17. Krakowski AC, Eichenfield LF, Dohil MA. Management of atopic dermatitis in the pediatric population. Pediatrics 2008; 122:812. 18. Jones SM, Sampson HA. The role of allergens in atopic dermatitis. Clin Rev Allergy 1993; 11:471. 19. Bleehen SS, Chu AC, Hamann I, et al. Fluticasone propionate 0.05% cream in the treatment of atopic eczema: a multicentre study comparing once-daily treatment and once-daily vehicle cream application versus twice-daily treatment. Br J Dermatol 1995; 133:592. 20. Koopmans, B, Lasthein Andersen, B, Mork, NJ, et al. Multicentre randomized double-blind study of locoid lipocream fatty cream twice daily versus locoid lipocream once daily and locobase once daily. J Dermatol Treat 1995; 6:103. 21. Green C, Colquitt JL, Kirby J, Davidson P. Topical corticosteroids for atopic eczema: clinical and cost effectiveness of once-daily vs. more frequent use. Br J Dermatol 2005; 152:130. 22. Berth-Jones J, Damstra RJ, Golsch S, et al. Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study. BMJ 2003; 326:1367. 23. Glazenburg EJ, Wolkerstorfer A, Gerretsen AL, et al. Efficacy and safety of fluticasone propionate 0.005% ointment in the long-term maintenance treatment of children with atopic dermatitis: differences between boys and girls? Pediatr Allergy Immunol 2009; 20:59. 24. Ashcroft DM, Dimmock P, Garside R, et al. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials. BMJ 2005; 330:516. 25. Nakagawa H. Comparison of the efficacy and safety of 0.1% tacrolimus ointment with topical corticosteroids in adult patients with atopic dermatitis: review of randomised, double-blind clinical studies conducted in Japan. Clin Drug Investig 2006; 26:235. 26. Aoyama H, Tabata N, Tanaka M, et al. Successful treatment of resistant facial lesions of atopic dermatitis with 0.1% FK506 ointment. Br J Dermatol 1995; 133:494.

27. Ruzicka T, Bieber T, Schpf E, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. European Tacrolimus Multicenter Atopic Dermatitis Study Group. N Engl J Med 1997; 337:816. 28. Reitamo S. Tacrolimus: a new topical immunomodulatory therapy for atopic dermatitis. J Allergy Clin Immunol 2001; 107:445. 29. Reitamo S, Rustin M, Ruzicka T, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis. J Allergy Clin Immunol 2002; 109:547. 30. Fonacier L, Spergel J, Charlesworth EN, et al. Report of the Topical Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 2005; 115:1249. 31. Wollenberg A, Sharma S, von Bubnoff D, et al. Topical tacrolimus (FK506) leads to profound phenotypic and functional alterations of epidermal antigen-presenting dendritic cells in atopic dermatitis. J Allergy Clin Immunol 2001; 107:519. 32. Reitamo S, Wollenberg A, Schpf E, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. The European Tacrolimus Ointment Study Group. Arch Dermatol 2000; 136:999. 33. Hanifin JM, Ling MR, Langley R, et al. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy. J Am Acad Dermatol 2001; 44:S28. 34. Reitamo S, Ortonne JP, Sand C, et al. A multicentre, randomized, double-blind, controlled study of long-term treatment with 0.1% tacrolimus ointment in adults with moderate to severe atopic dermatitis. Br J Dermatol 2005; 152:1282. 35. Rikkers SM, Holland GN, Drayton GE, et al. Topical tacrolimus treatment of atopic eyelid disease. Am J Ophthalmol 2003; 135:297. 36. Papp KA, Breuer K, Meurer M, et al. Long-term treatment of atopic dermatitis with pimecrolimus cream 1% in infants does not interfere with the development of protective antibodies after vaccination. J Am Acad Dermatol 2005; 52:247. 37. Eichenfield LF, Lucky AW, Boguniewicz M, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002; 46:495. 38. Wahn U, Bos JD, Goodfield M, et al. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 2002; 110:e2. 39. Gollnick H, Kaufmann R, Stough D, et al. Pimecrolimus cream 1% in the long-term management of adult atopic dermatitis: prevention of flare progression. A randomized controlled trial. Br J Dermatol 2008; 158:1083.

40. Kempers S, Boguniewicz M, Carter E, et al. A randomized investigator-blinded study comparing pimecrolimus cream 1% with tacrolimus ointment 0.03% in the treatment of pediatric patients with moderate atopic dermatitis. J Am Acad Dermatol 2004; 51:515. 41. Paller AS, Lebwohl M, Fleischer AB Jr, et al. Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: results from 3 randomized, comparative studies. J Am Acad Dermatol 2005; 52:810. 42. Doss N, Kamoun MR, Dubertret L, et al. Efficacy of tacrolimus 0.03% ointment as second-line treatment for children with moderate-to-severe atopic dermatitis: evidence from a randomized, doubleblind non-inferiority trial vs. fluticasone 0.005% ointment. Pediatr Allergy Immunol 2010; 21:321. 43. Boguniewicz M, Fiedler VC, Raimer S, et al. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. Pediatric Tacrolimus Study Group. J Allergy Clin Immunol 1998; 102:637. 44. Reitamo S, Van Leent EJ, Ho V, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunol 2002; 109:539. 45. www.fda.gov/cder/drug/advisory/elidel_protopic.htm (Accessed 5/8/07). 46. www.fda.gov/bbs/topics/news/2006/NEW01299.html (Accessed 5/8/07). 47. Berger TG, Duvic M, Van Voorhees AS, et al. The use of topical calcineurin inhibitors in dermatology: safety concerns. Report of the American Academy of Dermatology Association Task Force. J Am Acad Dermatol 2006; 54:818. 48. Margolis DJ, Hoffstad O, Bilker W. Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults. Dermatology 2007; 214:289. 49. Arellano FM, Wentworth CE, Arana A, et al. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol 2007; 127:808. 50. Ring J, Mhrenschlager M, Henkel V. The US FDA 'black box' warning for topical calcineurin inhibitors: an ongoing controversy. Drug Saf 2008; 31:185. 51. Jekler J, Lark O. Combined UVA-UVB versus UVB phototherapy for atopic dermatitis: a pairedcomparison study. J Am Acad Dermatol 1990; 22:49. 52. Reynolds NJ, Franklin V, Gray JC, et al. Narrow-band ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomised controlled trial. Lancet 2001; 357:2012. 53. Grundmann-Kollmann M, Behrens S, Podda M, et al. Phototherapy for atopic eczema with narrowband UVB. J Am Acad Dermatol 1999; 40:995.

54. Majoie IM, Oldhoff JM, van Weelden H, et al. Narrowband ultraviolet B and medium-dose ultraviolet A1 are equally effective in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol 2009; 60:77. 55. Meduri NB, Vandergriff T, Rasmussen H, Jacobe H. Phototherapy in the management of atopic dermatitis: a systematic review. Photodermatol Photoimmunol Photomed 2007; 23:106. 56. Gambichler T, Othlinghaus N, Tomi NS, et al. Medium-dose ultraviolet (UV) A1 vs. narrowband UVB phototherapy in atopic eczema: a randomized crossover study. Br J Dermatol 2009; 160:652. 57. Stern RS, Nichols KT, Vkev LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. N Engl J Med 1997; 336:1041. 58. Stern RS, Laird N, Melski J, et al. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med 1984; 310:1156. 59. Lindelf B, Sigurgeirsson B, Tegner E, et al. PUVA and cancer: a large-scale epidemiological study. Lancet 1991; 338:91. 60. de Prost Y. Atopic dermatitis: recent therapeutic advances. Pediatr Dermatol 1992; 9:386. 61. Czech W, Brutigam M, Weidinger G, Schpf E. A body-weight-independent dosing regimen of cyclosporine microemulsion is effective in severe atopic dermatitis and improves the quality of life. J Am Acad Dermatol 2000; 42:653. 62. Harper JI, Ahmed I, Barclay G, et al. Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy. Br J Dermatol 2000; 142:52. 63. Wolff K, Fleming C, Hanifin J, et al. Efficacy and tolerability of three different doses of oral pimecrolimus in the treatment of moderate to severe atopic dermatitis: a randomized controlled trial. Br J Dermatol 2005; 152:1296. 64. De Rie MA, Meinardi MM, Bos JD. Lack of efficacy of topical cyclosporin A in atopic dermatitis and allergic contact dermatitis. Acta Derm Venereol 1991; 71:452. 65. Meggitt SJ, Gray JC, Reynolds NJ. Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial. Lancet 2006; 367:839. 66. Stainer R, Matthews S, Arshad SH, et al. Efficacy and acceptability of a new topical skin lotion of sodium cromoglicate (Altoderm) in atopic dermatitis in children aged 2-12 years: a double-blind, randomized, placebo-controlled trial. Br J Dermatol 2005; 152:334. 67. Viljanen M, Savilahti E, Haahtela T, et al. Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial. Allergy 2005; 60:494.

68. Kopp MV, Hennemuth I, Heinzmann A, Urbanek R. Randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of Lactobacillus GG supplementation. Pediatrics 2008; 121:e850. 69. Boyle RJ, Bath-Hextall FJ, Leonardi-Bee J, et al. Probiotics for treating eczema. Cochrane Database Syst Rev 2008; :CD006135. 70. van der Aa LB, Heymans HS, van Aalderen WM, Sprikkelman AB. Probiotics and prebiotics in atopic dermatitis: review of the theoretical background and clinical evidence. Pediatr Allergy Immunol 2010; 21:e355. 71. van Gool CJ, Zeegers MP, Thijs C. Oral essential fatty acid supplementation in atopic dermatitis-a meta-analysis of placebo-controlled trials. Br J Dermatol 2004; 150:728. 72. Zhang W, Leonard T, Bath-Hextall F, et al. Chinese herbal medicine for atopic eczema. Cochrane Database Syst Rev 2004; :CD002291. 73. Lane JE, Cheyney JM, Lane TN, et al. Treatment of recalcitrant atopic dermatitis with omalizumab. J Am Acad Dermatol 2006; 54:68. 74. Weinberg JM, Siegfried EC. Successful treatment of severe atopic dermatitis in a child and an adult with the T-cell modulator efalizumab. Arch Dermatol 2006; 142:555. 75. Takiguchi R, Tofte S, Simpson B, et al. Efalizumab for severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol 2007; 56:222. 76. Simon D, Hsli S, Kostylina G, et al. Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol 2008; 121:122. 77. www.fda.gov/bbs/topics/NEWS/2009/NEW01992.html (Accessed on April 10, 2009). 78. Huang JT, Abrams M, Tlougan B, et al. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics 2009; 123:e808. 79. Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002; 347:1151. 80. Lebon A, Labout JA, Verbrugh HA, et al. Role of Staphylococcus aureus nasal colonization in atopic dermatitis in infants: the Generation R Study. Arch Pediatr Adolesc Med 2009; 163:745. 81. Suh LM, Honig PJ, Yan AC. Methicillin-resistant Staphylococcus aureus skin abscesses in a pediatric patient with atopic dermatitis: a case report. Cutis 2006; 78:113. 82. Suh L, Coffin S, Leckerman KH, et al. Methicillin-resistant Staphylococcus aureus colonization in children with atopic dermatitis. Pediatr Dermatol 2008; 25:528.

83. Chung HJ, Jeon HS, Sung H, et al. Epidemiological characteristics of methicillin-resistant Staphylococcus aureus isolates from children with eczematous atopic dermatitis lesions. J Clin Microbiol 2008; 46:991. 84. Leung, DY, Eichenfield, LF, Boguniewicz, M. Atopic dermatitis (Atopic eczema). In: Fitzpatrick's Dermatology in General Medicine, 7th ed, Wolff, K, Goldsmith, LA, Katz, SI, et al (Eds), McGraw-Hill 2008. p.146. 85. Metry, D, Browning, J, Rousseau et al. Sodium hypochlorite (bleach) baths: a potential measure to reduce the incidence of recurrent, cutaneous staphylococcus aureus superinfection among susceptible populations. Poster presented at the Society for Pediatric Dermatology annual meeting, Chicago, IL, July 12-15, 2007. 86. Birnie AJ, Bath-Hextall FJ, Ravenscroft JC, Williams HC. Interventions to reduce Staphylococcus aureus in the management of atopic eczema. Cochrane Database Syst Rev 2008; :CD003871. 87. Darabi K, Hostetler SG, Bechtel MA, Zirwas M. The role of Malassezia in atopic dermatitis affecting the head and neck of adults. J Am Acad Dermatol 2009; 60:125.

2011 UpToDate, Inc. All rights reserved. | Subscription and License Agreement Licensed to: k g

You might also like