Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

79. Atopic Dermatitis

Rebecca M. Law and Po Gin Kwa


KEY CONCEPTS

 Images Atopic dermatitis is a chronic skin disorder involving inflammation associated with intense pruritus, a hallmark symptom. Management of atopic dermatitis must always include appropriate management of the associated pruritus.

 Images Atopic dermatitis is associated with other atopic diseases such as asthma and allergic rhinitis in the same patient or family. The three conditions are known as the atopic triad.

 Images The prevalence of atopic dermatitis appears to have increased two- to threefold in many developed and developing countries during the last three decades. Recent data indicate age and country or regional differences, with some countries showing no change or even a decrease. Rural areas appear to have lower prevalence rates.

 Images There are genetic and environmental factors in the pathogenesis and pathophysiologic manifestations of atopic dermatitis. The inheritance pattern is not straightforward. More than one gene may be involved in the disease, with the filaggrin gene (FLG) being a key player.

 Images Atopic dermatitis often presents in infants and young children. The clinical presentation differs somewhat depending on the age of the patient.

 Images Secondary bacterial skin infections are common in patients with atopic dermatitis and must be promptly treated.

 Images Management of atopic dermatitis must always include appropriate nonpharmacologic management of any controllable environmental factors, such as avoidance of identified triggers. These may include aeroallergens (e.g., mold, grass, pollen), foods (e.g., peanuts, eggs, tomatoes), chemicals (e.g., detergents, soaps), clothing material (e.g., wool, polyester), temperature (e.g., excessive heat), and humidity (e.g., low humidity).

 Images Nonpharmacologic management of atopic dermatitis entails managing the symptoms associated with pruritus and encouraging appropriate skin care habits such as proper bathing techniques and the copious use of moisturizers, which is a standard of care.

 Images Topical corticosteroids are the drugs of first choice for atopic dermatitis.

 Images Topical calcineurin inhibitors (tacrolimus and pimecrolimus) are alternate treatment options for adults and children over the age of 2 years.

 Images This chronic illness has substantial socioeconomic impact. The cost may be magnified by undertreatment.


Images Atopic dermatitis (AD) is a common skin disease. It is often referred to as eczema, which is a general term for several types of skin inflammation. AD is the most common type of eczema (Table 79–1).1It is a chronic skin disorder involving inflammation with pruritus as the hallmark symptom and presentation. This disorder is often the prelude to atopic diathesis, which includes asthma and other allergic diseases.

TABLE 79-1 Types of Eczema (Dermatitis)1

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Images This form of dermatitis is commonly associated with other atopic disorders, such as allergic rhinitis and asthma. AD, allergic rhinoconjunctivitis, and asthma are known collectively as the atopic triad.2AD has also been defined as the cutaneous manifestation of atopy.2

The disease can have periods of exacerbation, or flareups, followed by periods of remission. These flareups may be disruptive to the patient’s quality of life and may affect the entire family. Disease flareups are difficult to manage and may be complicated by secondary infections. About one-half (estimate up to 65%) of cases in children first manifest before age 1 year14; these cases are termed early onset atopic dermatitis.5 Approximately 85% of patients develop symptoms before age 5 years.1

Of the children with AD diagnosed before age 1 year, approximately 40% to 60% will have the same skin condition continuing into their adulthood.1,3

Onset after age 30 years is much less common and is often caused by exposure to harsh or wet conditions1 such as repeated skin trauma or exposure to harsh chemicals. In adults, the prevalence is believed to be 1% to 3%, with an overall lifetime prevalence of approximately 7%.1

EPIDEMIOLOGY

Images The prevalence of AD is generally said to have increased two- to threefold in developed and developing countries during the last three decades.5 Currently in developed countries, an estimated 15% to 30% of children and 2% to 10% of adults are affected.5,6 The prevalence appears to be increasing worldwide, as earlier prevalence rates were estimated at 10% to 15% in children.4

Images The largest international study of the prevalence of AD found both age and country differences in prevalence rates.7 This international study was the International Study of Asthma and Allergies in Childhood (ISAAC), which was conducted in three phases.8 ISAAC Phase One included 700,000 children from 156 centers in 56 countries between 1992 and 1998. ISAAC Phase Two studied allergic causes from 30 centers in 22 countries. ISAAC Phase Three repeated a multicountry cross-sectional survey (1999 to 2004) and included 187,943 children aged 6 to 7 years from 64 centers in 35 countries and 302,159 adolescents aged 13 to 14 years from 105 centers in 55 countries. For children aged 6 to 7 years, most countries showed an increase of 2 standard deviations (SDs) in mean annual prevalence over a 5- to 10-year period. In contrast, for adolescents aged 13 to 14 years, the trends differ from country to country. Large increases in prevalence were seen in developing countries (e.g., Mexico, Chile, Kenya, and Algeria, and seven countries in Southeast Asia). But in other countries with formerly very high prevalences, the mean annual prevalence in eczema symptoms has either leveled off or decreased. Most of the largest decreases (SD ≥2) in prevalence were reported from developed countries in northwest Europe, (e.g., the United Kingdom, Ireland, Sweden, Germany) and New Zealand.7 The ISAAC study has suggested that a maximum prevalence plateau of approximately 20% has emerged.7,8

There were no differences according to the sex of the study participant, or with gross national income at a country level.7 This is consistent with other reports that AD affects males and females at approximately the same rate.1There appears to be a lower prevalence of AD in rural areas when compared with urban areas, suggesting a link to the hygiene hypothesis, which postulates that the absence of early childhood exposure to infectious agents increases susceptibility to allergic diseases.911 In contrast, children attending daycare centers before 3 months of age have less atopy and asthma in later childhood,11,12 and areas with diffuse and chronic helminth infestations have a low prevalence of allergic diseases.11 In addition, a recent European birth cohort study involving 1,133 newborns showed that children born to farm families had a lower prevalence of sensitization to seasonal inhaled allergens such as grass pollen.13 Maternal exposure during pregnancy (i.e., prenatal exposure) to animal sheds correlated with the lower prevalence rate in the farm children.12 However, there were no differences in prevalence related to inhaled perennial allergens.

Reported risk factors associated with higher prevalence include urban environment, higher socioeconomic status, higher level of family education, a family history of AD, female gender (after age 6 years), and smaller family size.8

ETIOLOGY

Images AD is a complex genetic disease that arises from gene–gene and gene–environment interactions. There are two major groups of genes involved. First, there are the genes encoding for epidermal or other epithelial structural proteins. Second, there are genes encoding for the major elements of the immune system.5

The inheritance pattern is not straightforward. More than one gene is likely involved in the disease. There is an increased risk for a child to have AD if there is a family history of other atopic diseases, such as hay fever or asthma. The risk is significantly higher if both parents have an atopic disease.1 Studies of identical twins show that a person whose identical twin has AD is seven times more likely to have AD than someone in the general population.1 And a person whose fraternal twin has AD is three times more likely to have AD than someone in the general population.1 Another estimate is 80% concordance in monozygous twins and 20% in heterozygous twins.10

Thus, genetic predispositions to developing AD exist. Specifically, there are several possible genes on the chromosomes 3q21, 1q21, 16q, 17q25, 20p, and 3p26. Of these chromosomes, 1q21 has the highest linkage region. This region has a family of epithelium-related genes called the epidermal differentiation complex.5 One of these genes, the filaggrin gene (FLG), on chromosome 1q21.3, was initially identified as the gene involved in ichthyosis vulgaris, and several mutations of this gene were subsequently identified in European and Japanese patients with AD.14 FLG encodes for a key protein in epidermal differentiation. Mutations or deficiency of FLG results in an abnormality in permeability barrier function.15

Epidermal barrier dysfunction is a prerequisite for the penetration of high-molecular-weight allergens in pollens, house dust mite products, microbes, and food.5 In mice studies, this barrier abnormality alters thresholds for irritant and acute allergic contact dermatitis, and FLG deficiency predisposes to the development of an AD-like dermatosis.15 In humans, two common FLG variants (R501X and 2282de14) with an estimated combined allele frequency of about 6% have been identified in individuals of European descent.16 Eighteen other less common variants have also been identified in Europeans, with an additional 17 mutations restricted to individuals of Asian descent.16 Each of these variants leads to nonsense mutations which either prevent or severely diminish the production of filaggrin in the epidermis.16 Mutations of FLG seem to occur mainly in early onset AD patients and may be associated with the development of asthma in patients with AD.5,16 However, FLG mutations are identified in only 30% of European patients with AD; implying that other genetic mutations affecting other epidermal structures may be important (e.g., changes in the cornified envelope proteins involucrin and loricrin, or lipid composition).5

There are other genes encoding for the immune system that may be associated with AD, especially those found on chromosome 5q31-33.5 These genes code for cytokines that regulate IgE synthesis. Cytokines are produced mainly by type 1 and type 2 helper T cells. T-helper type 1 (TH1) cells produce cytokines, which suppress immunoglobulin E (IgE) production (e.g., interferon-γ and interleukin-12 [IL-12]).5 T-helper type 2 (TH2) cells produce cytokines, which increase IgE production (e.g., IL-5 and IL-13).5,17 In patients with AD, there is an imbalance between TH1 and TH2 immune responses. These patients are genetically predisposed to TH2 predominance, seen as increased TH2 cell activity.2,5,17 Increased TH2 activity causes the release of IL-3, IL-4, IL-5, IL-10, and IL-13, resulting in blood eosinophilia, increased serum IgE, and increased growth and development of mast cells.2,5,17,18 In addition, these cytokines affect the maturation of B cells and cause a genomic rearrangement in these cells that favors isotype class switching from immunoglobulin M (IgM) to IgE.5

In summary, recent data suggest that FLG deficiency alone can provoke a barrier abnormality in the epidermis and predispose to the development of dermatitis by enhancing allergen absorption through the skin.19 Furthermore, there appears to be complex relationships, including genetic and nongenetic risk factors, that modify an individual’s susceptibility to allergic disease.20 Complex genetic factors contribute to the increased susceptibility to AD (FLGmutations and gene–gene interactions). These, along with environmental factors (gene–environment interactions), result in the pathophysiologic changes and clinical presentations associated with AD.

PATHOPHYSIOLOGY

The initial mechanisms that trigger inflammatory changes in the skin in patients with AD are unknown. Neuropeptides, irritation, or pruritus-induced scratching may be causing the release of proinflammatory cytokines from keratinocytes. Alternatively, allergens in the epidermal barrier or in food may cause T-cell mediated but IgE-independent reactions. Allergen-specific IgE is not a prerequisite.5 Characteristic features in pathophysiology are skin barrier dysfunction, and immune deviation toward TH2 with subsequent increased IgE.10 The disease is further complicated by microbial colonization with pathologic organisms resulting in increased susceptibility for skin infections.10

Skin barrier dysfunction plays a critical role in the development of AD,10,21,22 and loss of function mutations in the skin structural protein filaggrin is a major risk factor.22 Other factors may include a deficiency of skin barrier proteins, increased peptidase activity, lack of certain protease inhibitors, and lipid abnormalities.22 There must be epidermal barrier dysfunction for high-molecular-weight allergens in pollens, house dust mite particles, microbes, and foods to penetrate the skin barrier. Atopic skin has reduced antimicrobial peptides (AMPs). AMPs are normally produced by keratinocytes, sebocytes, and mast cells, and they form a chemical shield on the surface of the skin. Reduced AMPs result in a diminished antimicrobial barrier, which correlates with increased susceptibility to infections and superinfections seen in these patients.23

On penetration of the epidermal barrier, allergens are met by dendritic cells (DCs). DCs are antigen-presenting cells populating the skin, respiratory tract, and mucosa of the GI tract (i.e., at the front line of pathogen entry).24 DCs then enhance TH2 polarization, resulting in increased production of IgE. Keratinocytes in the skin of patients with AD also produce high levels of an IL-7–like protein, which again drives dendritic cells to enhance TH2 polarization. Epidermal dendritic cells in patients with AD bear IgE and express its high-affinity receptor (FcεRI).2527 Serum IgE is often elevated in patients with AD,1,18 especially during an exacerbation.

However, on initial presentation, patients with early onset AD generally do not have increased IgE levels (i.e., there is no detectable IgE-mediated allergic sensitization). IgE-mediated allergic sensitization may occur several weeks or months after the initial AD lesions appear. Although in some children—mostly girls—this sensitization never occurs.5

Predisposing Factors

Several factors can predispose patients to development of AD. These include climate, infection, genetics, environmental aeroallergens, and food.

Hot and extremely cold climates are both poorly tolerated by patients with this condition. Dry weather, common in the winter, causes increased skin dryness. Hot weather causes increased sweating, resulting in pruritus.

Patients with AD are commonly colonized by Staphylococcus aureus bacteria. Clinical infections with S. aureus frequently cause flareups of AD.

As discussed previously, genetics plays a role in AD. Family history of AD is common.

Exposure to environmental aeroallergens is another risk factor. Dust mites, pollens, molds, cigarette smoke, and dander from animal hair or skin may worsen the symptoms of AD.1,18

The role of food as antigens in the pathogenesis of AD is controversial. Small amounts of environmental foods (low-dose exposure from foods on tabletops, hands, dust) may penetrate the skin barrier and be taken up by Langerhans cells, leading to TH2 responses and IgE production.28 However, early high-dose oral food consumption induces oral tolerance. The timing and balance of cutaneous and oral exposure determines whether a child will have allergy or tolerance.28 Increased serum IgE antibodies to a particular food is evidence of sensitization to a food and is consistent with although not proof of a food allergy.1,29 Eczema may frequently be a manifestation of food allergy,28 and patients with AD have a higher prevalence of food allergy than those in the general population.1 Conversely, a current belief is that food allergy may be caused by AD, and in most patients with coexisting AD and food allergy, AD precedes the food allergy. Regardless, the two conditions coexist, and the likelihood of an infant or child with AD also having food allergy or allergies must be kept in mind.29

There is a known epidermal barrier dysfunction in AD, allowing for increased low-level skin permeability to allergenic foods. Certain foods may trigger acute reactions, including urticaria and anaphylaxis. The most commonly reported allergenic foods are eggs, milk, peanuts, wheat, soy, tree nuts, shellfish, and fish.1 Individual food allergies, such as peanut allergy, have increased in prevalence in the last decade;28,29 new food allergies may also be increasing in prevalence, particularly kiwi allergy28,30 and sesame seed allergy.28,31 Consistent with the oral tolerance concept, early results from recent studies using sublingual and oral immunotherapy to specific food allergens (e.g., milk or peanut) appear to indicate that it may be possible to induce oral tolerance, and that it may be possible to desensitize children to some allergenic foods. Currently, these treatment protocols have only been done in highly supervised research settings and with small numbers of patients.32 For more information about management of food allergies the reader is directed to the 2010 National Institute of Allergy and Infectious Diseases (NIAID)-sponsored expert panel’s report, available at www.niaid.nih.gov.29

CLINICAL PRESENTATION

Diagnosis of AD is generally based on clinical presentation (Table 79–2).1 There is no objective diagnostic test for the clinical confirmation of AD.1,33 Filaggrin gene mutations may be associated with persistent and more severe AD as well as early onset cases.22

TABLE 79-2 Skin Features Associated with Atopic Dermatitis1

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Clinical Controversy…

Although it has traditionally been thought that food allergies are a predisposing factor for the development of atopic dermatitis, some clinicians are now thinking that atopic dermatitis may be the predisposing factor for the development of food allergies in an individual. Often the signs and symptoms of atopic dermatitis appear before the food allergies.

Images The course of AD varies significantly over time. Studies reviewing the natural course of the disease usually describe the disease pattern as persistent, intermittent, or in remission.8 A 2004 study found that 43% were in complete remission after age 2 years, with 19% having persistent disease and 38% an intermittent pattern.8

The clinical presentation of AD differs depending on the age of the patient. In infancy, the earliest onset of AD usually occurs between 2 and 6 months of age, and especially between the 6th and 12th weeks of life.1,2 It has been reported that 75% of cases have their onset within the first 6 months.2 A more conservative estimate is that at least 65% of patients develop symptoms within the first year of life, and at least 85% will have developed symptoms before the age of 5 years.1 The initial presentation in infancy is an erythematous, papular skin rash that may first appear on the cheeks and chin as a patchy facial rash1,2and that can progress to red, scaling, oozing skin.1 The rash shows a centrifugal distribution affecting the malar region of the cheeks, forehead, scalp, chin, and behind the ears while sparing the central areas (i.e., the nose and paranasal creases).2 Lesions occur in the flexor surfaces, such as antecubital and popliteal fossae. Over the next few weeks and as the infant becomes more mobile and begins crawling, the lesions spread to the extensors of the lower legs, and eventually the entire body may be involved, with sparing of the diaper area and the nose.1 These lesions are associated with uncontrollable itchiness, and the infant will become irritable and may try to rub his or her face to relieve the itch. Scratching may occur quite early, and infants with AD may scratch themselves continuously, mainly when they are undressed or during sleep.2 Excessive rubbing or scratching may result in excoriation and development of secondary infections.

In childhood, the skin often appears dry, flaky, rough, cracked, and may bleed because of scratching. With repeated scratching and rubbing the skin becomes lichenified. Lichenification, usually localized to the flexural folds of the extremities,33 is characteristic of childhood AD in older children and adults.33,34 Lichenification signifies repeated rubbing of the skin and is seen mostly over the folds, bony protuberances, and forehead.34 Excoriations and crusting are also commonly seen, along with secondary infections. Sometimes increased folds are seen underneath the eyes (so-called Dennie–Morgan folds).34Lesions are still most commonly seen in the flexor surfaces of the body, particularly the flexural creases of the antecubital and popliteal fossae.34

Sleep disturbances also occur. One study reported that there are both brief and longer awakenings associated with scratching episodes that affect sleep efficiency in school-age children with AD.35

In adulthood, lesions are more diffuse with underlying erythema. The face is commonly involved and may be dry and scaly. Lichenification may again be seen. A brown macular ring around the neck, representing a localized deposit of amyloid, is typical but not always present.34

Although no objective diagnostic test confirms presence of AD,1 some signs, symptoms, and other factors are commonly used in its diagnosis. These include pruritus, early age of onset, eczematous skin lesions that vary with age, chronic and relapsing courses, dry and flaky skin, IgE reactivity, family or personal history of asthma or hay fever, or other atopic diseases (Table 79–3).18 In addition, allergy skin testing may be helpful in identifying factors that trigger flares of AD.1 Negative results may help rule out certain substances as triggers; however, positive results may be unrelated to disease activity, and false positives are common.1

TABLE 79-3 Major and Minor Signs and Symptoms of Atopic Dermatitis 1

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Images Pruritus is a quintessential feature of AD, and a diagnosis cannot be made if there is no history of itching.14 AD has been called the itch that, when scratched, erupts.2 Scratching or rubbing itchy, atopic skin characterizes this type of eczema.2 Scratching and rubbing further irritates the skin, increases inflammation, and exacerbates itchiness.3 Atopic skin can itch during sleep. This nighttime itching is a problem for many children with the disease, since there is no conscious control of scratching during sleep.1,18,35

Pruritus can be triggered by a variety of factors. The most common triggers of itch have been reported as heat and perspiration (96%), wool (91%), emotional stress (81%), certain foods (49%), alcohol (44%), upper respiratory infections (36%), and house dust mites (>35%).36

Once pruritus occurs, the surrounding normally nonpruritic skin area (whether inflamed or noninflamed) may be very sensitive and react to light stimuli and begin itching (allokinesis). Allokinesis is typical of AD.18,36 As a result of allokinesis, patients with AD may experience pruritic attacks when their skin is touched accidentally by mechanical factors such as clothing,18 especially wool products.36

Elevated serum IgE may be seen, consistent with the genetically predetermined dominance of TH2 cytokines causing increased IgE. In addition, increased serum IgE antibodies to a particular food, consistent with a food allergy,3is common in patients with AD. The radioallergosorbent test (RAST) is an allergen-specific IgE antibody test used to screen for allergy to a specific substance or substances. In some cases the RAST test may be used to monitor immunotherapy or to see if a child has outgrown a specific allergy. Positive (elevated) RAST usually indicates an allergy to a suspected or known allergen. However, the level of IgE may not correlate with the severity of an allergic reaction, and the IgE level may remain elevated for years after an allergy has been outgrown.18

A clinically useful set of criteria for the diagnosis of AD is as follows: atopy, pruritus, eczema, and altered vascular reactivity.18,36

COMPLICATIONS

Images Patients with AD are prone to skin infections. Atopic skin is drier and the stratum corneum has weakened protective abilities; combined with the abnormal skin barrier function and immune defense, there is an increased risk of secondary bacterial skin infections with staphylococci or streptococci, and viral infections such as herpes simplex or even fungal infections.1 Constant scratching to relieve pruritus may cause excoriations, further compromising the integrity of the skin barrier. S. aureus is a common cause of secondary bacterial infections in AD.10 Binding of S. aureus is enhanced by skin inflammation as seen in AD.21 Many patients with AD are colonized with S. aureus and may have exacerbations after skin infections of this organism.10,21 Secondary bacterial infections may present as yellowish crusty lesions and should be promptly treated. Oral (systemic) antibiotics are generally more effective than topical treatment.1,21

Patients with AD are also more prone to disseminated infections with herpes simplex or vaccinia virus.21 Severe viral infections such as eczema herpeticum or eczema vaccinatum might be linked to the severity of atopy.21Smallpox vaccination is contraindicated in patients with AD.21

TREATMENT

Desired Outcomes

In treating patients with AD, clinicians generally have the following clinical goals in mind:

   1. Provide symptomatic relief—control the itching.

   2. Control the AD.

   3. Identify and, when possible, eliminate triggers and environmental aeroallergens.

   4. Identify and minimize predisposing factors for exacerbations including any stressors.

   5. Prevent future exacerbations.

   6. Provide any social and psychological support needed for the patient, family, and caregivers.

   7. Minimize or prevent adverse events from medications and other treatment modalities.

   8. Treat to cure any secondary skin infections, if present.

Successful management of AD should include not only clearance of skin lesions, which may take days to weeks depending on the severity of disease, but also control of the itch, minimizing or eliminating triggers, monitoring the patient to minimize or prevent adverse events from medications or other treatment modalities, and providing adequate social and psychological support for the patient, family, and caregivers.

The ultimate goal is to provide enough control of this chronic disease so that future exacerbations are prevented, thus ensuring thatthe patient’s quality of life is minimally affected by AD. Because the course of the disease evolves over time, management strategies maychange.

Images Both nonpharmacologic and pharmacologic therapies are important in managing the signs and symptoms of AD. Nonpharmacologic strategies include identifying and minimizing or eliminating preventable risk factors, such as known triggers and allergens, as well as appropriate skin care.

Treatment guidelines and protocols for AD are available. These are listed in Table 79–4.

TABLE 79-4 Useful Sources of Information about Treatment of Atopic Dermatitis

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Nonpharmacologic Therapy

Images Nonpharmacologic approaches to the treatment of infants and children with AD include the following1:

   1. Give lukewarm baths.

   2. Apply lubricant immediately after bathing (moisturizers are a standard of care).9,10

   3. Keep child’s fingernails filed short.

   4. Select clothing made of soft cotton fabrics.

   5. Consider using sedating antihistamines to reduce scratching at night.

   6. Keep the child cool; avoid situations in which overheating occurs.

   7. Learn to recognize skin infections and seek treatment promptly.

   8. Attempt to distract the child with activities to keep him or her from scratching.

   9. Identify and remove irritants and allergens.

Hydration is crucial, and adequate skin hydration is a fundamental part of managing AD.3 Transepidermal water loss is greater in atopic skin than in normal skin. Thus, any measures to improve skin moisturization, such as liberal use of moisturizers, would be beneficial. Moisturizers are a standard of care and may be steroid-sparing.9,10,3740 They are useful for both prevention and maintenance therapy.9,10,39,40 They can be categorized based on their specific effects on the skin:

   1. Occlusives: These agents provide an oily layer on the skin surface to slow transepidermal water loss, increasing the moisture content of the stratum corneum. These are the best moisturizers for patients with AD.3

   2. Humectants: In the stratum corneum, these agents increase the water-holding capacity. However, they are not useful in patients with AD because they have a stinging effect on open skin.3

   3.Emollients: These agents smooth out the surface of the skin by filling the spaces with droplets of oil. These are the least effective moisturizers.3

Note that the term “emollients” is sometimes more broadly used to mean all nonmedicated moisturizers, including occlusives.37,38 Usual active ingredients in moisturizers include mineral oil, petrolatum, ceramide, and urea. Ceramide was shown to improve pruritus and sleep in pediatric patients with AD.38

The humidity in the home should be kept at or above 50% and the room temperature kept on the cool side.18

Appropriate skin care is crucial in preventing flareups.1 A daily skin care routine should include the following18:

   1. Using scent-free moisturizers liberally as needed each day. Large quantities can be used, and currently there are no recommendations regarding the appropriate amount or dosing frequency of moisturizers.38

   2. Bathing in lukewarm water (never hot) for about 5 minutes10 once or twice daily.3,37 Adding a capful of emulsifying oil10 may help the body retain moisture; baths are better than showers. Bathing daily for 10 to 20 minutes may be desirable as long as a thick moisturizer is applied afterward.37 Bathing twice daily during disease flares may be a useful method for enhancing skin penetration of topical therapies and for debridement of crusting and staphylococcal colonization.37 If showering, mild liquid cleansers are preferred over soaps.3

   3. The skin should be lightly towel dried (pat to dry, avoid rubbing or brisk drying).1,37,38

   4. Scent-free moisturizer should then be applied while the skin is still moist or slightly damp (within 3 minutes of towel drying).3,37 Some fragrance-free moisturizers include Aveeno Baby Soothing Relief Moisture Cream, Cetaphil, Neutrogena Hand Cream, and Vanicream products. Lotions may be used on the scalp and other hairy areas and for mild dryness on the face, trunk, and limbs; creams are more occlusive than lotions; ointments are the most occlusive and can be used for drier, thicker, or more scaly areas.3 Occlusive moisturizers are best.3

   5. Using nonsoap skin cleansers1 may cause less skin irritation. Lipid- and fragrance-free skin cleansers may be particularly advantageous (e.g., Cetaphil Gentle Skin Cleanser, Free and Clear Liquid Cleanser, Spectro Derm Cleanser). Aquanil, Dove, Neutrogena, and pHisoderm sensitive skin products have also been recommended as low-irritant products, and some are lipid free.

   6. Avoiding alcohol-containing topical products including lotions, swabs, and wipes, as they may be drying.

   7. Clothing should be double-rinsed. Mild detergents should be used to wash clothing, with no bleach or fabric softener.3

Pharmacologic Therapy

Topical Corticosteroids

ImagesTopical corticosteroids are the standard of care to which other treatments are compared.9,10,3740 They remain the drug treatment of choice for AD. However, despite their extensive use, supporting data are limited regarding optimal corticosteroid concentrations, duration and frequency of therapy, and quantity of application.9,10 The use of long-term intermittent application of topical corticosteroids was beneficial and safe in two randomized controlled trials (RCTs); however, independent studies of other formulations are needed.

To maximize the antiinflammatory benefit and minimize adverse effects, the choice of corticosteroid should be matched with the severity and site of disease.3 Low-potency corticosteroids, such as hydrocortisone 1%, are suitable for the face, and medium-potency corticosteroids, such as betamethasone valerate 0.1%, may be used for the body.3 For longer-duration maintenance therapy, low-potency corticosteroids are recommended.33 Mid-strength and high-potency corticosteroids should be used for short-term management of exacerbations.33 Ultrahigh- and high-potency corticosteroids, such as betamethasone dipropionate 0.05% or clobetasone propionate 0.05%, are typically reserved for short-term treatment of lichenified areas in adults.39 Short-term treatments mean brief periods of 1 to 2 weeks.37,38 After the lesions have cleared or significantly improved, a lower-potency steroid should be used for maintenance when necessary.39 Potent fluorinated corticosteroids should be avoided not only on the face, but also the genitalia and the intertriginous areas, and in young infants.33 (For a corticosteroid potency comparison chart, see Table 78–2 in the chapter on psoriasis, or visit the National Psoriasis Foundation website at http://www.psoriasis.org/netcommunity/sublearn03_mild_potency.)

It is also important to remember that altering the local environment through hydration and/or occlusion as well as changing the vehicle41 may alter the absorption and effectiveness of the topical corticosteroid.10 Some vehicles are better suited for certain body areas,41 such as a lotion for the scalp and hairy areas. Foams may be more cosmetically pleasing to some patients, as they easily disappear into the skin. The surface area of the skin involved and the skin thickness also play a role.33 In addition, tachyphylaxis is a clinical concern, but there is no experimental documentation.

Adverse effects of topical corticosteroids may be systemic in nature, and they are directly related to the steroid potency, duration of use, and other factors as discussed above. Local adverse effects include striae and skin atrophy, perioral dermatitis, acne, rosacea, telangiectasias, and allergic contact dermatitis (often related to the vehicle).33,42 The potential for systemic adverse effects is related to the potency of the topical corticosteroid, the site of application, the occlusiveness of the preparation, the percentage of body surface area covered, and the duration of use.33 Potential systemic effects include hypothalamic-pituitary-adrenal (HPA) axis suppression, infections, hyperglycemia, cataracts, glaucoma, and growth retardation (in children).1,3,9,18,37,38,42 However, growth retardation may also be related to the chronicity of the illness rather than to corticosteroid use or dietary factors.3 Although less likely, systemic adverse effects can occur with low-potency topical corticosteroids. For example, a phase II study of a mild-potency corticosteroid (desonide 0.05% foam) in children and adolescents 3 months to 17 years showed that 4% (3 of 75) of patients experienced mild reversible HPA-axis suppression after a 4-week treatment period.43

When topical steroid therapy has failed for efficacy or safety reasons, numerous agents and interventions can be used as alternative or add-on therapy in patients with AD.

Topical Calcineurin Inhibitors

Images Topical immunomodulators such as the calcineurin inhibitors tacrolimus ointment (Protopic) and pimecrolimus cream (Elidel) have been shown to reduce the extent, severity, and symptoms of AD in adults and children.10,39,40Tacrolimus has been reported to inhibit the activation of key cells involved in AD, including T cells, dendritic cells, mast cells, and keratinocytes.33 Pimecrolimus acts similarly to tacrolimus, inhibiting T-cell proliferation, preventing gene transcription of TH1 and TH2 cytokines, and reducing mediator release from mast cells and basophils.33 However, pimecrolimus has more favorable lipophilic characteristics and, in animal studies, appears to preferentially distribute to the skin as opposed to the systemic circulation.33,44 Both tacrolimus ointment and pimecrolimus cream are approved for AD in adults and children older than age 2 years.3,10,39,40,44 Although clinical trials conducted in younger infants (e.g., 2 to 23 months old) also showed significant efficacy without appreciable adverse effects, use in children younger than age 2 years is not FDA approved.45 Tacrolimus 0.03% ointment is approved for moderate-to-severe AD for ages 2 years and older, with the 0.1% ointment limited to ages 16 years and older; pimecrolimus 1% cream is approved for mild-to-moderate AD for ages 2 years and older.45 There is limited data comparing topical corticosteroids with tacrolimus or pimecrolimus.

Because of continuing concerns regarding a possible risk of cancer with tacrolimus and pimecrolimus,45 both drugs are recommended for use as second-line treatments in AD,9,10,3740 when the continued use of topical corticosteroids is ineffective or inadvisable.37 They may be appropriate in patients with corticosteroid-related adverse effects, patients with large body-surface areas of disease, patients unresponsive to corticosteroids, or other reasons where treatment with corticosteroids is inadvisable.3 Children and adults with a weakened or compromised immune system should not be treated with these agents. Unlike topical corticosteroids, calcineurin inhibitors can be used on all body locations for prolonged periods,3,10 although episodic use is recommended. Skin atrophy does not occur.33

The most common adverse effect of topical calcineurin inhibitors is transient discomfort (burning sensation) at the application site.3 There is a potential for local skin carcinogenesis as seen in animal studies, or for systemic effects if high blood levels are reached (e.g., increased susceptibility to infections due to immunosuppressive effects).45 Because there is a possible risk of cutaneous malignancy,3,37 sun protection is recommended.3,18,37,45 Patients should be encouraged to apply a high sun protection factor (SPF) broad-spectrum sunblock daily to all exposed skin (e.g., SPF 30 or higher); and this counseling should especially be emphasized for those patients with the highest risk of developing skin cancer, including patients with red hair and/or Fitzpatrick skin types I and II, and patients receiving phototherapy or using tanning beds.45

Topical calcineurin inhibitors are very effective in relieving the associated pruritus. Both tacrolimus and pimecrolimus significantly relieve pruritus even after the first few days of treatment in both children and adults (studies report relief after just 3 days).10


Clinical Controversy…

With topical calcineurin inhibitors, there is a potential for local skin carcinogenesis as seen in animal and in vitro studies. In addition, pigmented melanocytic lesions have been seen in treated areas, raising concern about melanoma.43 The FDA has a black box warning for both tacrolimus ointment and pimecrolimus cream about their potential cancer risk, but no causal relationship has been proven between use of a topical calcineurin inhibitor and the development of lymphoma or nonmelanoma skin cancer.43

Phototherapy

Phototherapy is effective for AD and is recommended10,3740 especially when the disease is not controlled by tacrolimus or pimecrolimus ointment. Phototherapy may be steroid sparing, allowing for the use of lower-potency topical corticosteroids, or even eliminating the need for maintenance corticosteroids in some cases. Phototherapy may also help prevent secondary bacterial skin infections, commonly seen in patients with AD. However, in a few patients, phototherapy may worsen the AD; it is not recommended in patients whose disease flares up when exposed to sunlight. Relapse following cessation of therapy frequently occurs.10

Phototherapy may consist of either ultraviolet light therapy alone, or ultraviolet light therapy alongside drug or topical ointment (commonly called photochemotherapy). Psoralens plus ultraviolet A light (PUVA) is one type of photochemotherapy. The photosensitizer (psoralens) is administered either orally or in a bath immediately prior to ultraviolet A (UVA) light therapy. Topical ointments (such as crude coal tar) may also be used concomitantly with ultraviolet light therapy (e.g., Crude coal tar + ultraviolet B [UVB] light).

Ultraviolet lamps include UVA (315 to 400 nm), UVA1 (340 to 400 nm), broadband UVB (BB-UVB) (280 to 315 nm), and narrowband UVB (NB-UVB) (311 nm). Phototherapies used for AD have included PUVA, high- or medium-dose UVA1, BB-UVB, and NB-UVB.10,46 There is weaker evidence supporting the use of PUVA in AD46 and it is not a first-choice therapy.10 NB-UVB is more effective than BB-UVB therapy and is preferred.10 BB-UVB may not effectively treat the scalp and skinfold areas. Medium-dose UVA1 is very effective for patients with an acute exacerbation of severe AD; however, the effect may be relatively short-lived and symptoms may recur within 3 months of stopping therapy.46 An adult study comparing medium-dose UVA1 and NB-UVB found no difference in efficacy; however, the sample size was quite small (N = 13), and the follow-up period was confounded by the use of topical corticosteroids.47 Currently, medium-dose UVA1 is considered similar in efficacy as NB-UVB; and high-dose UVA1 is preferred in severe phases.10

Patients need to wear eye protection during ultraviolet (UV) light therapy to prevent damage to the retina. Short-term adverse effects include erythema, skin pain, skin burning or sunburn, pruritus, and pigmentation.33 Long-term adverse effects include premature aging of the skin (photoaging) and skin cancer.33,46 For example, PUVA has been associated with squamous cell carcinoma and possibly melanoma, which may occur years after PUVA therapy has ceased.46

Coal Tar

Although tar preparations had been widely used for AD and have been recommended as alternative topical therapy, few RCTs support their efficacy.33 Their antiinflammatory properties are not well characterized, and part of the improvement with the agent may be the result of a placebo effect, which can be significant in AD.33

Coal tar products are also staining and malodorous, although newer products may be more cosmetically acceptable. They are not recommended on acutely inflamed skin, since this may result in additional skin irritation.33

The use of coal tar in pregnancy has not been studied. Few data are available about tar excretion into breast milk; in addition, safety in children has not been established.48 Adverse effects include tar folliculitis, acneiform eruptions, irritant dermatitis, burning, stinging, photosensitivity, and a risk of tar intoxication if used extensively in a young child.48 Although animal studies showed that tar components can be converted to carcinogenic and mutagenic entities, there is inconclusive epidemiologic evidence supporting the claim that human use of topical tar preparations in dermatology leads to skin cancer.48


Clinical Controversy…

Animal studies showed that coal tar components can be converted to carcinogenic/mutagenic entities, and tar keratoses (small nodules that develop from cutaneous tar exposure) have the potential to regress, fall off, or develop into a squamous cell carcinoma. However, there is inconclusive epidemiologic evidence supporting the claim that human use of topical tar preparations in dermatology leads to skin or internal cancers such as bladder cancer or lymphoma.48

Systemic Therapies

Systemic therapies for the treatment of AD are generally not well studied or approved by FDA or Health Canada. Small case series or open studies are available for some agents, but few well-conducted RCTs exist. Agents described in published papers have included systemic corticosteroids, cyclosporine, interferon-γ, azathioprine, methotrexate, mycophenolate mofetil, intravenous immunoglobulin (IVIG), and more recently biologic response modifiers.10

Systemic corticosteroids, such as oral prednisone, rarely may be required as a short-term treatment10 for severe, recalcitrant, chronic AD.33 Although not routinely recommended,3740 systemic corticosteroids can provide rapid relief of severe refractory disease during transition to other therapies.46 The dosage of the drug must be tapered during discontinuance to minimize a rebound flareup.33,38 Intensified skin care, particularly with topical corticosteroids and moisturizers, is also important during the taper to minimize a rebound flareup.33

Cyclosporine is considered effective for severe AD,10 but its usefulness is limited by significant side effects, including hypertension and nephrotoxicity. There is also the potential for significant drug–drug and drug–food (e.g., grapefruit juice) interactions. It should be reserved for short-term use in adults or children with severe refractory disease.46 Maximal benefit is usually seen after approximately 2 weeks of use and relapse may occur quickly after cessation of therapy.10,46 In a meta-analysis of eight RCTs, cyclosporine is more efficacious than placebo, with reduced body surface area, erythema, sleep loss, and glucocorticoid use. However, all scores were back to pretreatment levels 8 weeks after ending cyclosporine therapy.10

Recombinant interferon-γ may be effective in a subset of patients with AD.10 Two randomized placebo-controlled trials in patients with severe AD demonstrated significant improvement in symptoms.49,50Short-term adverse effects, such as headache, myalgias, and chills, occurred in substantial proportions of study patients. Transient liver transaminase elevations and granulocytopenia have also occurred.51Long-term therapy (up to 24 months) did not appear to be associated with significant adverse events.33 Some recommend that a higher dose of this agent be used initially followed by a lower dosage during maintenance therapy.46

Azathioprine,33,52 methotrexate,53 mycophenolate mofetil33 andIVIG have shown efficacy in small case series or open-label studies primarily in adults with recalcitrant AD. They are rarely used. Oral methotrexate, with a long history of pediatric use for various inflammatory conditions, appeared to be effective in a case series of children (aged 2 to 16 years) with severe AD.53

Biologic response modifiers, unlike for psoriasis, are currently not approved for AD. The safety and efficacy of various biologic response modifiers in patients with AD have been studied,51 mostly in case reports, small case series, or open-label studies with a limited number of patients. Theoretically, using protein-based therapies is inherently risky in a patient population more prone to developing IgE sensitization to protein antigens than the general population. Type 1 immediate hypersensitivity reactions such as anaphylaxis could result, and patients with severe disease are potentially the patients at greatest risk of anaphylaxis. None has been reported in the published literature, which detail 261 patients with AD treated with various biologics,51 but these numbers are too small to generalize their findings to larger numbers of people or specific populations.

More specifically, the TNF-α inhibitors infliximab and etanercept appeared effective in a few patients but not others, and adverse events have included infusion reactions with flushing and dyspnea, urticaria, and recurrent skin infections of methicillin-resistant S.aureus. Similarly, omalizumab, rituximab, and alefacept have been shown in a few case reports and small case series to be somewhat effective.

Additional research is needed to determine the therapeutic potential and safety of biologics in patients with AD.51

Complementary and Alternative Therapies

Traditional Chinese herbal therapy has been studied in placebo-controlled trials and appeared to provide temporary benefit for patients with severe AD. However, the effectiveness may wear off despite continued treatment, and long-term toxicity is unknown.10,33,54,55

Mycobacterium vaccae (killed) injected intradermally was found to be effective in reducing the severity of skin disease in a placebo-controlled trial in children with moderate-to-severe AD.56 This suggests that downregulation of the TH2 response in AD may potentially be beneficial.33

Probiotics of various types have been studied in several RCTs with mixed results. One study group reported that prenatal and postnatal exposure for 6 months to Lactobacillus rhamnosus GG halved the frequency of AD at 2, 4, and 7 years but had no effect on atopic sensitization. Other study groups also administered lactobacilli, including L. rhamnosus GG, but with mixed results. A recent placebo-controlled study comparing Bifidobacterium lactis and L. rhamnosus HN001 found that L. rhamnosus HN001 may be effective in preventing the development of AD in high-risk infants, but not Bifidobacterium. However, one study showed that Lactobacillus acidophilus supplementation actually increased the sensitization rate (40% vs. 24%) and led to more IgE-associated AD.57 More research is needed about the role of probiotics in prevention and treatment of AD.57

Immunotherapy using allergen-specific desensitization techniques in controlled settings for patients with AD may also be beneficial, and much research is ongoing. Double-blind controlled studies have not shown consistent efficacy.

More research is also needed to adequately assess the role of homeopathy, hypnotherapy, acupuncture, massage therapy, and biofeedback therapy in the treatment of AD.

PERSONALIZED PHARMACOTHERAPY

Images AD may have significant implications not only for the patients themselves, but also their families and caregivers.

In 2006, an international study of 2,002 patients and caregivers from eight countries addressed the effect of AD on the lives of patients and society.58 This European study found that, on average, patients experienced nine flares per year, with those having severe disease experiencing more flares and taking significantly longer to clear. The flares were associated with disturbed sleep, and 86% of patients avoided at least one type of everyday activity. Schoolwork performance and productivity were negatively affected. Patients missed an average of 2.5 days of school or work per year, and an analysis of adult patient performance at work and occupational absence showed that the social cost of lost productivity could amount to more than 2 billion Euros per year across the European Union. There were also emotional consequences; half of the patients experienced depression or unhappiness about their condition, and one-third reported that AD had eroded their self-confidence. In addition, concern about adverse effects from topical corticosteroid treatments resulted in poor adherence to therapy. On average, patients endured the symptoms of AD without initiating specific treatment 47% of the time they had an exacerbation. Approximately one-half of the respondents were concerned about using topical corticosteroids, and 58% restricted them to particular sites, 39% used them less frequently or for shorter time periods than prescribed, and 66% used them as a last resort. The study concluded that AD is “an undertreated disease that has a significant, yet mostly avoidable, negative effect on patients, their caregivers, and society.”58

Thus, healthcare professionals play an integral role in providing patient and caregiver education about this disease and specific treatment plans. The importance of adequate and appropriate education for the patient, family, and caregivers about AD and its management cannot be overemphasized. Patients should be involved in their own care.

CONCLUSION

AD is a chronic skin condition that generally presents at an early age. It affects the patient, family, and caregivers. Nonpharmacologic management strategies are important in treatment; these include appropriate skin care, hydration, avoidance of triggers, and psychosocial support. Pharmacologic treatment emphasizes topical corticosteroids as the standard of care. Patient and caregiver education about AD and treatment strategies is critical to minimize nonadherence. Successful outcomes result when patients and caregivers are partners with healthcare professionals in the management of this chronic disease.

ACKNOWLEDGMENT

Portions of this chapter have been adapted with permission from reference 18.

ABBREVIATIONS

Images

REFERENCES

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