GUIDELINES OF CARE FOR THE MANAGEMENT OF ATOPIC DERMATITIS

Abstract

Atopic dermatitis (AD) is a common and chronic, pruritic inflammatory skin condition that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this second of four sections, treatment of AD with non-pharmacological interventions and pharmacological topical therapies are reviewed. Where possible, suggestions on dosing and monitoring are given based on available evidence.

METHOD

A work group of recognized AD experts was convened to determine the audience and scope of the guideline, and to identify important clinical questions in the use of topical therapies for AD management (Table I). Work group members completed a disclosure of interests which was updated and reviewed for potential relevant conflicts of interest throughout guideline development. If a potential conflict was noted, the work group member recused him or herself from discussion and drafting of recommendations pertinent to the topic area of the disclosed interest.

Table I.

Clinical questions used to structure the evidence review for the management and treatment of atopic dermatitis with topical therapies

What is the effectiveness of non-pharmacological interventions such as moisturizers, prescription emollient devices, bathing practices and oils, and wet-wraps for the treatment of atopic dermatitis? What is the efficacy, optimal dose, frequency of application, and adverse effects of the following agents used as monotherapy or in combination with other topical agents for the treatment of atopic dermatitis? ▪ Topical corticosteroids ▪ Topical calcineurin inhibitors ▪ Topical antimicrobials/antiseptics ▪ Topical antihistamines ▪ Others (e.g. coal tar, phosphodiesterase inhibitors)

An evidence-based approach was used and evidence was obtained using a systematic search of PubMed, the Cochrane Library, and the Global Resources for Eczema Trials (GREAT)¹ databases from November 2003 through November 2012 for clinical questions addressed in the previous version of this guideline published in 2004, and 1964–2012 for all newly identified clinical questions. Searches were prospectively limited to publications in the English language. MeSH terms used in various combinations in the literature search included: atopic dermatitis, atopic eczema, topical agents, topicals, non-pharmacological, barrier, emollient, moisturizer, bathing, oil, topical corticosteroid, hydrocortisone, calcineurin inhibitor, tacrolimus, pimecrolimus, coal tar, phosphodiesterase inhibitors, antimicrobial, antiseptic, retapamulin, triclosan, chlorhexidine, beta-thujaplicin, mupirocin, triclocarban, antibacterial soap, topical antibiotic, pseudomonic acid, and potassium permanganate.

A total of 1,789 abstracts were initially assessed for possible inclusion. After removal of duplicate data, 246 were retained for final review based on relevancy and the highest level of available evidence for the outlined clinical questions. Evidence tables were generated for these studies and utilized by the work group in developing recommendations. The Academy’s prior published guidelines on AD were also evaluated, as were other current published guidelines on atopic dermatitis.^2–5

The available evidence was evaluated using a unified system called the Strength of Recommendation Taxonomy (SORT) developed by editors of the U.S. family medicine and primary care journals (i.e. American Family Physician, Family Medicine, Journal of Family Practice, and BMJ USA).⁶ Evidence was graded using a 3-point scale based on the quality of study methodology (e.g. randomized control trial, case-control, prospective/retrospective cohort, case series, etc.), and the overall focus of the study (i.e. diagnosis, treatment/prevention/screening, or prognosis) as follows:

1. Good-quality patient-oriented evidence (i.e. evidence measuring outcomes that matter to patients: morbidity, mortality, symptom improvement, cost reduction, and quality of life).

2. Limited-quality patient-oriented evidence.

3. Other evidence including consensus guidelines, opinion, case studies, or disease-oriented evidence (i.e. evidence measuring intermediate, physiologic, or surrogate end points that may or may not reflect improvements in patient outcomes).

Clinical recommendations were developed based on the best available evidence tabled in the guideline. These are ranked as follows:

1. Recommendation based on consistent and good-quality patient-oriented evidence.

2. Recommendation based on inconsistent or limited-quality patient-oriented evidence.

3. Recommendation based on consensus, opinion, case studies, or disease-oriented evidence.

In those situations where documented evidence-based data was not available, expert opinion was utilized to generate clinical recommendations.

This guideline has been developed in accordance with the American Academy of Dermatology (AAD)/AAD Association Administrative Regulations for Evidence-based Clinical Practice Guidelines (version approved May 2010), which includes the opportunity for review and comment by the entire AAD membership and final review and approval by the AAD Board of Directors.⁷ This guideline will be considered current for a period of five years from the date of publication, unless reaffirmed, updated, or retired at or before that time.

DEFINITION

Atopic dermatitis is a chronic, pruritic inflammatory skin disease that occurs most frequently in children, but also affects many adults. It follows a relapsing course. AD is often associated with elevated serum immunoglobulin (IgE) levels and a personal or family history of type I allergies, allergic rhinitis, and asthma. Atopic eczema is synonymous with AD.

INTRODUCTION

Topical agents are the mainstay of atopic dermatitis therapy. Even in more severe cases needing systemic or phototherapy, they are often used in conjunction with these modalities. While discussed in separate subsections, topical agents from several classes are frequently used in combination, in part because they address different aspects of AD pathogenesis. Each class of treatment is discussed in regards to its mode of action and main use in therapy, and where possible, suggestions on dosing and monitoring are given based on available evidence.

NON-PHARMACOLOGICAL INTERVENTIONS

Moisturizers

Xerosis is one of the cardinal clinical features of AD and results from a dysfunctional epidermal barrier. Topical moisturizers are used to combat xerosis and transepidermal water loss, with traditional agents containing varying amounts of emollient, occlusive, and/or humectant ingredients. Although they often include water as well, this only delivers a transient effect, while the other components provide the main benefits.⁸ Emollients (e.g. glycol and glyceryl stearate, soy sterols) lubricate and soften the skin, occlusive agents (e.g. petrolatum, dimethicone, mineral oil) form a layer to retard evaporation of water, while humectants (e.g. glycerol, lactic acid, urea) attract and hold water.

The application of moisturizers increases hydration of the skin, as measured subjectively by patients and objectively by assessment of capacitance or conductance and with microscopy.^8–12 In addition, a number of clinical trials have shown that they lessen symptoms and signs of AD, including pruritus, erythema, fissuring, and lichenification. ^9–13 Thus, moisturizers can themselves give some reduction in inflammation and AD severity. Furthermore, their use decreases the amount of prescription anti-inflammatory treatments required for disease control, as demonstrated in three randomized controlled trials (RCTs).^13–15 Moisturizers can be the main primary treatment for mild disease and should be part of the regimen for moderate and severe disease.¹⁶ They are also an important component of maintenance treatment and prevention of flares (further discussed in Part 4). Moisturizers are therefore a cornerstone of AD therapy and should be included in management plans (recommendations summarized in Table II and level of evidence in Table VIII).

Table II.

Recommendation for non-pharmacological interventions for the treatment of atopic dermatitis

The application of moisturizers should be an integral part of the treatment of patients with atopic dermatitis as there is strong evidence that their use can reduce disease severity and the need for pharmacologic intervention.

Bathing is suggested for patients with AD as part of treatment and maintenance; however, there is no standard for the frequency or duration of bathing appropriate for those with AD.

Moisturizers should be applied soon after bathing to improve skin hydration in patients with AD.

Limited use of non-soap cleansers (that are neutral to low pH, hypoallergenic, and fragrance-free) is recommended.

For the treatment of patients with AD, the addition of oils, emollients, and most other additives to bath water and the use of acidic spring water cannot be recommended at this time, due to insufficient evidence.

Use of wet-wrap therapy with or without a topical corticosteroid can be recommended for patients with moderate to severe AD to decrease disease severity and water loss during flares.

Table VIII.

Strength of recommendations for the use of topical therapies in the treatment of atopic dermatitis

Recommendation	Strength of Recommendation	Level of Evidence	References
Use of moisturizers	A	I	9–16, 18–21, 126
Bathing and bathing practices	C	III	23, 24, 26, 28, 30
Application of moisturizers after bathing	B	II	24, 25
Limited use of non-soap cleansers	C	III	27–30
Against use of bath additives, acidic spring water	C	III	31, 32, 127
Wet wrap therapy	B	II	34–41
Use of topical corticosteroids (TCS)	A	I	42–46
Consideration of a variety of factors in TCS selection	C	III	49, 128, 129
Frequency of application	B	II	51–53
Proactive use of TCS for maintenance	B	II	54–56
Need for consideration of side effects with use	A	I	57, 58, 66
Need for monitoring for cutaneous side effects with potent TCS	B	III	57, 58, 66
Specific routine monitoring for systemic side effects with TCS not needed	C	III	57, 58, 62, 66
Addressing fears with use	B	III	67–69
Use of topical calcineurin inhibitors (TCIs)	A	I	70, 76, 81
Use as steroid-sparing agents	A	I	82, 83
Off-label use of TCIs in those under 2 years of age	A	I	76, 89
Counseling on local reactions with TCIs and the preceding use of TCS	B	II	81, 85, 96
Proactive use of TCIs for maintenance	A	I	54, 93–95
Concomitant TCS and TCI use	B	II	82, 83, 106–109
Informing patients regarding theoretical risk of cutaneous viral infections with use	C	III	82, 98
Awareness of black box warning of TCIs	C	III	98–101
Routine monitoring of TCI blood levels not needed	A	I	102, 103
Against routine use of topical antistaphylococcal treatments	A	I	110–112
Bleach baths and intranasal mupirocin for those with moderate to severe AD and clinical infection	B	II	113
Against use of topical antihistamines	B	II	42, 115–117

There is a lack of systematic studies to define an optimal amount or frequency of application of moisturizers.¹⁷ It is generally felt that liberal and frequent reapplication is necessary such that xerosis is minimal. Traditional moisturizers are formulated into a variety of delivery systems, including creams, ointments, oils, gels, and lotions. While most ointments have the advantage of not containing preservatives, which may cause stinging when applied to inflamed skin, they may be too greasy for some AD patients. Lotions have a higher water content that can evaporate and may be less ideal in those with significant xerosis.

Prescription emollient devices (PEDs) are a newer class of topical agents designed to target specific defects in skin barrier function observed in AD. They include preparations having distinct ratios of lipids that mimic endogenous compositions and creams containing palmitoylethanolamide, glycyrrhetinic acid, or other hydrolipids. They are generally recommended for two or three times daily use depending on the specific agent. While there is some evidence that PEDs also lessen symptoms and signs of AD, including xerosis and inflammation, they have only been tested in a small number of controlled studies.^{16, 18–20} They are approved as 510(k) medical devices based on the assertion that they serve a structural role in skin barrier function and do not exert their effects by any chemical actions. This approval process requires less rigorous clinical efficacy data than that needed for Food and Drug Administration (FDA) approval of drugs. In addition, these agents are more costly, although they are considered safe adjunctive treatments. There are now several moisturizers containing ceramides and/or filaggrin breakdown products which are available over-the-counter (OTC), though the compositions are not necessarily equivalent to those of the PEDs.

Head-to-head trials between specific moisturizing products are few in number, and those performed to date have not demonstrated one to be superior to others, including the PEDs. One study of 39 subjects with mild to moderate AD found no difference in efficacy between glycyrrhetinic acid-containing hydrolipid cream, 3:1:1 ceramide:cholesterol:free fatty acids cream, and an OTC petroleum-based skin protectant moisturizer when used for 3 weeks.²¹ Another study showed similar parity for an OTC oil-based moisturizing cream and a palmitoylethanolamide-containing PED over a 4-week application period.¹⁶ Therefore, the choice of moisturizing agent is highly dependent on individual preference. The ideal agent should be safe, effective, inexpensive, and free of additives, fragrances, perfumes, and other potentially sensitizing agents. But regardless of the particular product used, moisturizing to address the defective barrier is an important therapeutic concept given our current understanding of AD pathogenesis. Trials are also underway to test if skin barrier protection and moisturizer use from birth reduces the likelihood of development of AD in genetically predisposed infants.²²

Bathing Practices, including Additives

Bathing can have differing effects on the skin depending on the manner in which it is carried out. Bathing with water can hydrate the skin and remove scale, crust, irritants, and allergens, which can be helpful for patients with AD.²³ However, if the water is left to evaporate from the skin, greater transepidermal water loss occurs.²⁴ Therefore, application of moisturizers soon after bathing is necessary to maintain good hydration status.^{24, 25}

There is little objective data from which to determine best bathing practices, and most recommendations stem from expert consensus and personal experience. The recommendations of the current work group are summarized in Table II (level of evidence in Table VIII). Although one survey²⁶ of children found that more AD patients shower as opposed to bathe in a tub, over 80% of subjects were over the age of 5 years, likely influencing the results, and there are no comparative studies to suggest one particular form of bathing as better. There is also no clear frequency or duration of bathing that is optimal for those with AD. However, it is generally recommended that up to once daily bathing be performed to remove serous crust, as long as moisturizers follow as above; the duration should be limited to short periods of time (such as 5 to 10 minutes) with use of warm water. If there are areas of significantly inflamed skin, soaking in plain water for 20 minutes followed by the immediate application of pharmacological anti-inflammatory therapies (such as topical corticosteroids, TCS) to these sites, without toweling dry, is a helpful treatment measure. This “soak and smear” technique can improve response in cases where the topical anti-inflammatory alone is inadequate.²³

Limited use of non-soap cleansers that are neutral to low pH, hypoallergenic, and fragrance-free is recommended. Soaps consist of surfactants that interact with stratum corneum proteins and lipids, but in a manner that causes damage, dry skin, and irritation.^{27, 28} Most soaps are alkaline in pH, while the skin’s normal pH is 4 to 5.5. Instead, non-soap based surfactants and synthetic detergents (syndets) are often recommended for better tolerance, although this is based on only a few supportive clinical studies.^{29, 30}

With the exception of bleach, which is discussed in detail below, data is limited on the addition of oils, emollients, and other related additives to bath water and their benefits for AD.^{26, 31} The quantity of emollient deposited on the skin via a bath additive is likely to be lower than that from direct application. No published RCTs have tested the clinical benefit of combining bath emollients with directly applied emollients after bathing. Thus, at this time, the routine use of bath additives cannot be recommended. Use of acidic spring water for bathing (balneotherapy) also has limited supporting evidence.³² The use of water softening devices has also not been shown to have benefits over the use of normal water.³³

Wet Wrap Therapy

Wet wrap therapy (WWT) is one method to quickly reduce AD severity, and is often utilized in the setting of significant flares and/or recalcitrant disease. It may be performed on an ambulatory or inpatient basis.^{34, 35} Most use a technique of a topical agent that is covered by a wetted first layer of tubular bandages, gauze, or a cotton suit, followed by a dry second/outside layer. For more generalized disease, two layers of non-irritating clothing can be similarly prepared. WWT appears to help via occluding the topical agent for increased penetration, decreasing water loss, as well as providing a physical barrier against scratching. The wrap can be worn from several hours to 24 hours at a time, depending on patient tolerance. Most suggest several days of use, although a few studies continued WWT for up to 2 weeks.³⁵

In two comparative trials, the application of TCS with wet wraps was more efficacious than using only moisturizers with the wraps.^36,37 Care should be taken, however, when mid- to higher potency corticosteroids are applied under the wraps, as absorption is increased and may cause hypothalamic-pituitary-adrenal (HPA) axis suppression, especially if used widely on the skin. Temporary decreases in early morning serum cortisol levels have been reported, although short courses of use have not been associated with prolonged adrenal suppression.^{38, 39} Two studies showed that this risk could be decreased by limiting to once daily application or by diluting the potent TCS to 10% or even 5% of their original strength.^{37, 40} Some prefer to use low to medium potency TCS instead of dilution. The potential for increased risk of infection has been raised with the use of mid- to higher potency topical steroids in WWT, although the data is sparse and conflicting regarding its actual occurrence.^{35, 36, 41}

TOPICAL CORTICOSTEROIDS

Topical corticosteroids (TCS) are used in the management of AD in both adults and children and are the mainstay of anti-inflammatory therapy. They act on a variety of immune cells, including T lymphocytes, monocytes, macrophages, and dendritic cells, interfering with antigen processing and suppressing the release of pro-inflammatory cytokines. They are typically introduced into the treatment regimen after failure of lesions to respond to good skin care and regular use of moisturizers alone.

Efficacy

TCS have been used to treat AD for over 60 years. Their efficacy has been demonstrated with a wide variety of preparations and strengths, with more than 110 different RCTs performed to date.⁴² They are generally the standard to which other topical anti-inflammatory therapies are compared. In addition to decreasing acute and chronic signs of AD, multiple trials have shown decreased pruritus with their application.^43–46 TCS are utilized for both active inflammatory disease and for prevention of relapses. Comparative trials are limited in duration and scope (i.e. they mainly involve two, and occasionally three, agents), and as a result, there is no data to support one or a few specific agents as being more efficacious than others. Patient vehicle preference, along with cost and availability, often determine their selection. A summary of recommendations on TCS use is in Table III, with the level of evidence in Table VIII.

Table III.

Recommendations for the use of topical corticosteroids for the treatment of atopic dermatitis

Topical corticosteroids are recommended for AD-affected individuals who have failed to respond to good skin care and regular use of emollients alone.

A variety of factors should be considered when choosing a particular topical corticosteroid for the treatment of AD, including patient age, areas of the body to which the medication will be applied, and other patient factors such as degree of xerosis, patient preference, and cost of medication.

Twice daily application of corticosteroids is generally recommended for the treatment of AD; however, evidence suggests that once daily application of some corticosteroids may be sufficient.

Proactive, intermittent use of topical corticosteroids as maintenance therapy (1–2 times per week) on areas that commonly flare is recommended to help prevent relapses and is more effective than use of emollients alone.

The potential for both topical and systemic side effects, including possible hypothalamic-pituitary-adrenal (HPA) axis suppression, should be considered, particularly in children with AD in whom corticosteroids are used.

Monitoring by physical examination for cutaneous side effects during long-term, potent steroid use is recommended.

No specific monitoring for systemic side effects is routinely recommended for patients with atopic dermatitis.

Patient fears of side effects associated with the use of topical corticosteroids for AD should be recognized and addressed to improve adherence and avoid under-treatment.

Dosage

TCS are grouped into seven classes, from very low/lowest potency (VII) to very high potency (I), based on vasoconstriction assays. Table IV provides some representative examples of available agents in each class. There is a paucity of studies that examine a range of TCS doses in large numbers of patients and with the lack of an established optimum, great variability in dosing exists. Some use a short burst of a high-potency TCS to rapidly control active disease, followed by a quick taper in potency, while others use the lowest potency agent thought to be needed and adjust upward only if this fails.

Table IV.

Relative Potencies of Topical Corticosteroids^*

Class	Drug	Dosage Form(s)	Strength (%)
I. Very High Potency	Augmented betamethasone dipropionate	Ointment	0.05
	Clobetasol propionate	Cream, foam, ointment	0.05
	Diflorasone diacetate	Ointment	0.05
	Halobetasol propionate	Cream, ointment	0.05
II. High Potency	Amcinonide	Cream, lotion, ointment	0.1
	Augmented betamethasone dipropionate	Cream	0.05
	Betamethasone dipropionate	Cream, foam, ointment, solution	0.05
	Desoximetasone	Cream, ointment	0.25
	Desoximetasone	Gel	0.05
	Diflorasone diacetate	Cream	0.05
	Fluocinonide	Cream, gel, ointment, solution	0.05
	Halcinonide	Cream, ointment	0.1
	Mometasone furoate	Ointment	0.1
	Triamcinolone acetonide	Cream, ointment	0.5
III-IV. Medium Potency	Betamethasone valerate	Cream, foam, lotion, ointment	0.1
	Clocortolone pivalate	Cream	0.1
	Desoximetasone	Cream	0.05
	Fluocinolone acetonide	Cream, ointment	0.025
	Flurandrenolide	Cream, ointment	0.05
	Fluticasone propionate	Cream	0.05
	Fluticasone propionate	Ointment	0.005
	Mometasone furoate	Cream	0.1
	Triamcinolone acetonide	Cream, ointment	0.1
V. Lower-Medium Potency	Hydrocortisone butyrate	Cream, ointment, solution	0.1
	Hydrocortisone probutate	Cream	0.1
	Hydrocortisone valerate	Cream, ointment	0.2
	Prednicarbate	Cream	0.1
VI. Low Potency	Alclometasone dipropionate	Cream, ointment	0.05
	Desonide	Cream, gel, foam, ointment	0.05
	Fluocinolone acetonide	Cream, solution	0.01
VII. Lowest Potency	Dexamethasone	Cream	0.1
	Hydrocortisone	Cream, lotion, ointment, solution	0.25, 0.5, 1
	Hydrocortisone acetate	Cream, ointment	0.5–1

Reprinted with permission from Paller AS, Mancini AJ. Eczematous eruptions in childhood. In: Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. St. Louis, MO: Elsevier Inc; 2011 chapter 3, p.49.

^*Includes representative examples and not all available agent

No universal standard exists for quantity of application, although suggested methods include use of the adult finger-tip unit (the amount from the distal interphalangeal joint to the finger tip, or approximately 0.5g, being applied over an area equal to two adult palms), following the rule of 9’s that measures the percent affected area, and utilization of charts that propose amounts based on patient age and body site.^{47, 48}

Children have a proportionately greater body surface area to weight ratio, and as a result, have a higher degree of absorption for the same amount applied. But during significant acute flares, the use of mid- or higher potency TCS for short courses may be appropriate to gain rapid control of symptoms, even in children.^{49, 50} However, for long-term management, the least potent corticosteroid that is effective should be used to minimize the risk of adverse effects. Greater caution regarding TCS potency is also needed when treating thin skin sites (i.e. face, neck, and other skin folds), where there is greater penetration and higher likelihood for systemic absorption. It is important to monitor quantities of TCS used over time, which may impact efficacy and safety.

Frequency of Application

Most studies on the efficacy of topical corticosteroids in AD management involve twice daily application. This is the most common clinical practice and also the generally recommended frequency. However, there is evidence to suggest that once daily application of some potent corticosteroids may be as effective as twice daily application.⁵¹ Some newer formulations also use once daily application.^52,53

For acute flares, use of TCS is recommended every day until the inflammatory lesions are significantly improved and less thick, for up to several weeks at a time. After obtaining control of an outbreak, the goal is to prolong the period until the next flare. Previously, TCS use was stopped on improvement of symptoms and signs of disease, switching to the use of moisturizers alone and reinstituting the TCS only with subsequent relapses. However, in recent years, a more proactive approach to maintenance has been advocated for those patients who experience frequent, repeat outbreaks at the same body sites.^54–56 This entails the scheduled application of a TCS once to twice weekly at these particular locations, a method which has reduced rates of relapse and increased time to first flare relative to the use of moisturizers alone (to be discussed further in Part 4).

Adverse Effects and Monitoring

The incidence of reported side effects from TCS use is low; however, most studies fail to follow patients long-term for potential complications.⁵⁷ Cutaneous side effects include purpura, telangiectasias, striae, focal hypertrichosis, and acneiform or rosacea-like eruptions. Of greatest concern is skin atrophy, which can be induced by any TCS, though higher potency agents, occlusion, use on thinner skin, and older patient age increase this risk.^{57, 58} Many of these side effects will resolve after discontinuing TCS use, but may take months. Sites of treatment should be assessed regularly for these adverse effects, particularly with use of more potent agents. Continuous application of TCS for long periods of time should be avoided, to limit the occurrence of negative changes. Proactive, once to twice weekly application of mid-potency TCS for up to 40 weeks has not demonstrated these adverse events in clinical trials.⁵⁴

TCS application on AD lesions does reduce Staphylococcus aureus (S. aureus) bacterial load, likely via decreasing the inflammatory cytokines that inhibit antimicrobial peptide production.^{59, 60} There is some worry that TCS may impair the process of wound healing and re-epithelialization, although excoriated and fissured lesions should be included in treatment given that the underlying inflammation and pruritus lead to these secondary changes. Allergic contact dermatitis/type IV hypersensitivity can develop to TCS or other ingredients in their formulations, such as propylene glycol and preservatives. This should be considered if lesions fail to respond as expected or worsen with application. Patch testing is needed to determine if the allergen is the steroid compound itself or a component of the vehicle.⁶¹ Development of tachyphylaxis is of concern for some practitioners, where the efficacy is felt to decrease with repeated use of the same agent, though data is lacking to suggest that this is a significant clinical problem. While there is documented risk with systemic corticosteroid use, an association between topical steroid use and the development of cataracts or glaucoma is not as clear.⁵⁷ Nonetheless, minimizing use at periocular sites may be prudent.

Topically applied corticosteroids, particularly high- and very high-potency agents, can be absorbed at a degree sufficient to cause systemic side effects. The risk of HPA axis suppression is low but increases with prolonged continuous use, especially in individuals receiving corticosteroids concurrently in other forms (inhaled, intranasal or oral).⁶² As discussed above, children are more susceptible as a result of a greater body surface to weight ratio. There is also some concern for negative effects on linear growth, although reports have given mixed conclusions. ^63–65 Hyperglycemia and hypertension have rarely been reported.^{57, 66}

A systematic review concluded that TCS overall have a good safety profile.^57,66 No specific monitoring for systemic side effects is recommended for AD patients at this time. Hwever, if HPA axis suppression is a concern, this can be assessed by performing a cortisol stimulation test to check for appropriate adrenal response. As discussed in Part 1, some children with AD are underweight as a result of severe disease, although further decline in growth should prompt consideration for investigation.

Addressing Concerns with TCS Use

While judicious use of TCS is certainly warranted, recognition of under-treatment as a result of steroid phobia is also important. One survey of 200 dermatology outpatients with AD found that 72.5% were worried about use of TCS on their own or their child’s skin, with 24% admitting non-compliance with therapy as a result of these concerns.⁶⁷ Other studies have shown that patient knowledge of steroid class potencies is poor and leads to inappropriate use.^{68, 69} Thus, to achieve good response, it is important to address such fears and incorrect beliefs. The risks associated with TCS use do appear to be low with appropriate application and choice of potency, combined with periods of non-use.⁵⁷ A higher strength of recommendation (than actual level of evidence) is therefore placed on counseling, since the benefits outweigh the risks.

TOPICAL CALCINEURIN INHIBITORS

Topical calcineurin inhibitors (TCIs) are a second class of anti-inflammatory therapy introduced in 2000. They are naturally produced by Streptomyces bacteria and inhibit calcineurin-dependent T-cell activation, blocking the production of pro-inflammatory cytokines and mediators of the AD inflammatory reaction. They have also been demonstrated to affect mast cell activation, and tacrolimus decreases both the number and co-stimulatory ability of epidermal dendritic cells.⁷⁰

Efficacy

Two TCIs are available, topical tacrolimus ointment (0.03% and 0.1% strengths) and pimecrolimus cream (1% strength). Both agents have been shown to be more effective than vehicle in short-term (3 to 12 weeks) and long-term (up to 12 months) studies in adults and children with active disease.^71–76 Physician’s global evaluation scores showed decline, as well as the percent body surface area involved and patient evaluation of symptoms and signs of disease. Tacrolimus is approved for moderate to severe disease, while pimecrolimus is indicated for mild to moderate AD, and six-week comparative studies support a greater effect for tacrolimus over this time period for all AD severities.^77–80

A meta-analysis of 25 RCTs found tacrolimus 0.1% to be as effective as the mid-potency TCS hydrocortisone butyrate 0.1%, while tacrolimus 0.03% is less effective than hydrocortisone butyrate 0.1% but more effective than the low-potency TCS hydrocortisone acetate 1%.⁸¹ Pimecrolimus cream has not been directly compared to low potency TCS, but is less efficacious than mid- and high-potency TCS.^{76, 81}

Dosing

In the United States, the TCIs are approved as second-line therapy for the short term and non-continuous chronic treatment of AD in non-immunocompromised individuals who have failed to respond adequately to other topical prescription treatments for atopic dermatitis, or when those treatments are not advisable. TCIs have the benefit of not carrying risk for cutaneous atrophy, with little negative effect on collagen synthesis and skin thickness. TCIs can therefore be used as steroid-sparing agents and long-term studies to 12 months have shown that they do reduce the need for TCS use.^{82, 83} They have also been demonstrated to be more effective in reversing skin atrophy than vehicle.⁸⁴

TCIs have particular utility at sensitive skin sites, such as the face and skin folds, where there is a greater adverse risk profile with TCS. Three studies of pimecrolimus noted greater improvement at the face and neck compared to other body sites and in one RCT, more subjects achieved clearance of eyelid dermatitis using pimecrolimus compared to vehicle (45 vs. 19%).^84–87 In a 3-week RCT of tacrolimus 0.1% ointment compared to fluticasone 0.005% ointment in adults with moderate to severe facial AD in which conventional treatment was ineffective or poorly tolerated, tacrolimus gave greater improvement in the modified severity score.⁸⁸ Fewer patients opted to switch from tacrolimus to fluticasone than vice versa. Box 1 lists situations in which TCIs may be preferable to topical steroids.

Box 1.

Clinical situations in which TCIs may be preferable to topical steroids
Recalcitrance to steroids
Sensitive areas (e.g. face, anogenital, skin folds)
Steroid-induced atrophy
Long-term uninterrupted topical steroid use

Tacrolimus 0.03% ointment and pimecrolimus cream are indicated for use in individuals age 2 years and older, while tacrolimus 0.1% strength is only approved in those over age 15 years. However, evidence from clinical trials supports the safe and effective use of topical tacrolimus 0.03% and pimecrolimus in children less than 2 years of age, including in infants.⁷⁶ The indications for tacrolimus were based on early studies which suggested that the 0.03% and 0.1% strengths were equally effective and safe in children, although the 0.1% strength showed superiority in adults.^{89, 90} Subsequent clinical experience with the off-label use of tacrolimus 0.1% in children has led many to feel it is more effective than the 0.03% formulation, but there is a need for additional formal comparative studies.

Frequency of Application

Twice daily application of the tacrolimus ointments and pimecrolimus cream are significantly more effective at decreasing signs of inflammation, affected body surface area, and associated pruritus of lesional areas on the head/neck and non-head/neck locations than vehicle or once daily application in adults, children, and infants.^{91, 92}

Proactive, intermittent application of TCIs two to three times weekly to recurrent sites of disease has also been shown to be effective in reducing relapses. After gaining control of acute disease, topical tacrolimus (0.03% in children and 0.1% in adults) significantly reduced the number of exacerbations compared to vehicle, as well as increased the time to first exacerbation and the number of flare-free days.^93–95 It has been used for up to 1 year using this strategy, without significant adverse events noted.

Adverse Effects

The most common side effects seen are local reactions such as stinging and burning. These symptoms are more frequent than that seen with TCS, but tend to lessen after several applications or when first preceded by a short period of topical steroid use.⁹⁶ Patients should be advised of these adverse effects to avoid premature discontinuation of treatment. There are scattered reports of allergic contact dermatitis and a rosacea-like granulomatous reaction due to TCIs.

Patients with flaring and/or severe AD are at risk for secondary infections as a result of the skin disease (discussed further with Topical Antimicrobial/Antiseptics). The effect of continuation of TCI treatment on infected lesions has not been studied, but the prescribing information advocates against their use during acute infection. As with TCS, topical tacrolimus applied to non-infected lesions has been associated with reduced S. aureus colonization, also likely due to reduced inflammation and barrier dysfunction.⁹⁷ No consistent increases in the prevalence of cutaneous viral infections have been demonstrated with continuous or intermittent use of TCIs for up to 5 years.^{82, 83, 98} However, physicians should inform their patients of these theoretical risks given the lack of long-term safety data.

TCI boxed warning should be discussed with patients prior to use. Rare cases of malignancy (e.g. skin cancer and lymphoma) have been reported in patients treated with these agents, although a causal relationship has not been established. This warning was added in response to widespread off-label use in children under 2 years of age, as well as based on a theoretical risk from the use of high-dose oral calcineurin inhibitor therapy in post-transplant patients and from animal studies with exposures 25 to nearly 50-fold the maximum recommended human dose.⁹⁹ Interim analyses of ongoing, ten-year surveillance studies to address these concerns have not found evidence of increased malignancy rates relative to that expected in the general pediatric population.^{98, 99} Several studies, including a large case-control study of 293,253 patients, have noted an increased risk of lymphoma that correlates with AD severity, but not with TCI use.^{100, 101} Overall, the TCIs have demonstrated a good safety profile to date when used as recommended, but continued assessment is needed. Proactive guidance on the content of the black box warning can reduce anxiety on the part of patients and parents.

There is no evidence to suggest a need for routine blood monitoring of tacrolimus or pimecrolimus levels in AD patients. Both TCIs have shown consistently low to negligible systemic absorption following topical application, without any notable sequelae.^{102, 103} Use in conditions with a much more severely impaired skin barrier that would give increased absorption, such as with Netherton syndrome may warrant such monitoring.^{104, 105}

Use with Topical Corticosteroids

TCIs may be combined with TCS use in a number of ways. Often topical steroids are used first for control of a flare, given greater potency and also to reduce occurrence of some of the local symptoms associated with TCIs. TCIs can then be used both to spare topical steroid use as well as to prevent relapse. Only a few comparative trials have formally tested the TCS plus TCI combination, which may be used sequentially or concomitantly. In one study, four weeks of topical betamethasone butyrate propionate and tacrolimus sequential therapy improved lichenification and chronic papules to a greater degree than betamethasone butyrate propionate and emollient sequential therapy.¹⁰⁶ Tacrolimus 0.1% ointment used concomitantly with desoximetasone ointment was superior to tacrolimus and vehicle and the combination of clocortolone 0.1 % cream with tacrolimus 0.1 % ointment was also superior to either topical agent alone.^107,108 However, one study of pimecrolimus cream added to fluticasone 0.05% cream did not appear to offer any significant advantage in the treatment of AD flares.¹⁰⁹

Other studies have examined the use of continuous, daily TCI therapy between flares, particularly with topical pimecrolimus. Pimecrolimus application led to more days without flare, a decreased number of days needing TCS rescue, and an increased median time to first flare, compared to vehicle.^{82, 83} Recommendations for use are in Table V.

Table V.

Recommendations for the use of topical calcineurin inhibitors for the treatment of atopic dermatitis

Topical calcineurin inhibitors (TCIs) are recommended and effective for acute and chronic treatment, as well as maintenance, in both adults and children with atopic dermatitis, and are particularly useful in selected clinical situations (see Box 1).

TCIs are recommended for use on actively affected areas as a steroid-sparing agent for the treatment of AD.

For AD patients under 2 years of age with mild to severe disease, off-label use of 0.03% tacrolimus or 1% pimecrolimus ointment can be recommended.

Pimecrolimus cream and tacrolimus ointment may cause skin burning and pruritus, especially when applied to acutely inflamed skin. Initial treatment of AD patients with topical corticosteroids should be considered to minimize TCI application site reactions. Patients with AD should be counseled about the possibility of these reactions.

Proactive, intermittent use of TCIs as maintenance therapy (2–3 times per week) on areas that commonly flare is recommended to help prevent relapses while reducing the need for topical corticosteroids, and is more effective than the use of emollients alone.

The concomitant use of a topical corticosteroid with a topical calcineurin inhibitor may be recommended for the treatment of atopic dermatitis.

No consistent increases in the prevalence of cutaneous viral infections have been seen with continuous or intermittent use of TCIs for up to 5 years; however, physicians should inform their patients of these theoretical cutaneous risks, given the lack of safety data for longer periods of time.

Clinicians should be aware of the black box warning on the use of TCIs for AD patients and discuss as warranted.

Routine blood monitoring of tacrolimus and pimecrolimus levels in patients with AD who are applying these agents is not recommended at this time.

TOPICAL ANTIMICROBIALS & ANTISEPTICS

Atopic individuals are predisposed to skin infections due to a compromised physical barrier, coupled with diminished immune recognition and impaired antimicrobial peptide production. S. aureus, in particular, is a frequent culprit as well as colonizer of the skin in AD. Its presence, even without overt infection, appears to trigger multiple inflammatory cascades, via toxins that act as superantigens and exogenous protease inhibitors that further damage the epidermal barrier and potentiate allergen penetration.

A 2010 Cochrane review of RCTs found a lack of quality trials to support the use of antimicrobial and antiseptic preparations to treat AD (further discussed in Part 3).¹¹⁰ The review also did not find any clear benefit for topical antibiotics/antiseptics, antibacterial soaps, or antibacterial bath additives in either the setting of clinical infection or uninfected AD, noting that even positive findings in studies often had poor reporting of details. While the addition of a topical antibiotic to a topical steroid reduces the amount of S. aureus isolated from the skin, the combination has not been found to improve either global outcomes or disease severity compared to the steroid alone.^{59, 111, 112} Thus, topical antimicrobial preparations are not generally recommended in the treatment of AD (recommendation in Table VI, level of evidence in Table VIII). They can be associated with contact dermatitis, and there is also concern that their use could promote wider antimicrobial drug resistance.

Table VI.

Recommendations for the use of topical antimicrobials and antiseptics for the treatment of atopic dermatitis

Except for bleach baths with intranasal mupirocin, no topical antistaphylococcal treatment has been shown to be clinically helpful in patients with atopic dermatitis, and is not routinely recommended.

In patients with moderate to severe AD and clinical signs of secondary bacterial infection, bleach baths and intranasal mupirocin may be recommended to reduce disease severity.

An exception to the above antimicrobial agents is the use of bleach baths with intranasal topical mupirocin. In one RCT of 31 children with moderate to severe atopic dermatitis, treatment of an infectious episode with oral cephalexin for 2 weeks followed by the addition of household bleach to bathwater plus intranasal application of mupirocin for 3 months led to a greater improvement in disease severity than simple bathing alone.¹¹³ Enhanced clinical improvement was noted only in the skin submerged in the bath (not the head/face). Bleach baths may therefore be helpful in cases of moderate to severe disease with frequent bacterial infections, and particularly for maintenance, as cultures did not show clearance of the bacteria in the majority of patients. There is less concern about the development of bacterial resistance with use of dilute bleach relative to the use of topical and systemic antibiotics. Topical hypochlorite products are also available as an alternative to dilute bleach baths, but at higher cost and without any RCTs published to date.

In children and adults with clinically uninfected atopic dermatitis, the use of underwear made of silver impregnated textile did not reduce the severity of the atopic dermatitis compared to cotton underwear.¹¹⁴ Use of silk fabric with a durable antimicrobial finish has limited positive data, and needs further investigation.

TOPICAL ANTIHISTAMINES

Topical antihistamines have been tried for the treatment of AD but unfortunately have demonstrated little utility and are not recommended (see Table VII, level of evidence in Table VIII). Studies investigating topical doxepin have demonstrated a short-term decrease in pruritus in some cases, but with no significant reduction in disease severity or control. Treatment has local side effects, particularly stinging and burning, and can also cause sedation.^{115, 116} There are multiple reports of allergic contact dermatitis secondary to the use of topical doxepin; however, the specific incidence of this outcome cannot be established with certainty based on the available data.¹¹⁷ There are no controlled studies on the use of topical diphenhydramine for AD. It may also cause allergic or photoallergic contact dermatitis.¹¹⁸ Widespread application, use on broken skin, and/or combined use with oral diphenhydramine are not advised due to risk for systemic toxicities such as toxic psychosis (hallucinations, delirium, etc.), particularly in children.^{119, 120}

Table VII.

Recommendations for the use of topical antihistamines for the treatment of atopic dermatitis

The use of topical antihistamines for the treatment of patients with AD is not recommended due to the risk of absorption and of contact dermatitis.

OTHER TOPICAL AGENTS

Topical coal tar derivatives have been used for many years in the treatment of inflammatory skin diseases, particularly psoriasis. There are, however, very few trials of coal tar preparations and their efficacy in the treatment of AD.¹²¹ Munkvad investigated a preparation designed to be more cosmetically acceptable than traditional formulations and found it to be as effective as 1% hydrocortisone acetate cream on left/right paired comparison for mild to moderate disease.¹²² But given only a 4-week study and 5 of 30 patients reported itching and soreness, there is not adequate data to make a recommendation regarding the use of coal tar topical agents. A recent study of organotypic skin models from AD patients and controls did find that coal tar activates the aryl hydrocarbon receptor signaling pathway, resulting in enhanced epidermal differentiation, increased levels of filaggrin, and inhibition of a major AD cytokine pathway (interleukin-4/STAT6).¹²³

Topical phosphodiesterase inhibitors are another new class of anti-inflammatory treatments,^{124, 125} but remain available only in clinical trials, also precluding any recommendations for or against their use at this time.

GAPS IN RESEARCH

In review of the currently available highest level of evidence, the expert work group acknowledges that while much is known about the use of non-pharmacological and pharmacological topical therapies for AD, much has yet to be learned. Significant gaps in research were identified, including but not limited to: RCTs to better determine optimal bathing techniques, including controlled studies on frequency, duration, and the effects of bathing and use of bath emollients; well-designed, large trials to better test the effects of topical antimicrobial agents and TCS-TCIs in combination; and studies to provide additional long-term safety data on the use of TCIs. It is hoped that such gaps are closed to further optimize the utilization of topical therapeutic options.

SCOPE.

This guideline addresses the management of pediatric and adult atopic dermatitis (AD, atopic eczema) of all severities. The treatment of other forms of dermatitis, such as irritant dermatitis and allergic contact dermatitis in those without atopic dermatitis, are outside the scope of this document. Recommendations on AD treatment and management are subdivided into four sections given the significant breadth of the topic, and to update as well as expand on the clinical information and recommendations previously published in 2004. This document is the second part of the series and covers the use of non-pharmacological approaches (such as moisturizers, bathing practices, and wet wraps), along with pharmacological topical modalities, including corticosteroids, calcineurin inhibitors, antimicrobials, and antihistamines.

ABBREVIATIONS

AAD

American Academy of Dermatology

AD

atopic dermatitis

FDA

Food and Drug Administration

GREAT

Global Resources for Eczema Trials

HPA

hypothalamic-pituitary-adrenal

IgE

Immunoglobulin E

OTC

over-the-counter

PED

prescription emollient device

TCI

topical calcineurin inhibitors

TCS

topical corticosteroids

RCT

randomized controlled trial

SORT

Strength of Recommendation Taxonomy

WWT

wet wrap therapy

Publishable Conflict of Interest Statement

The American Academy of Dermatology (AAD) strives to produce clinical guidelines that reflect the best available evidence supplemented with the judgment of expert clinicians. Significant efforts are taken to minimize the potential for conflicts of interest to influence guideline content. Funding of guideline production by medical or pharmaceutical entities is prohibited, full disclosure is obtained and evaluated for all guideline contributors, and recusal is used to manage identified relationships. The AAD conflict of interest policy summary may be viewed at www.aad.org.

The below information represents the authors identified relationships with industry that are relevant to the guideline. Relevant relationships requiring recusal for the drafting of guideline recommendations for this section are noted where applicable for each author.

Lawrence F. Eichenfield, MD served as a consultant for Anacor, Bayer, Leo Pharma receiving honoraria , and TopMD receiving stock options; was a consultant and speaker for Galderma receiving honoraria; served as a consultant, speaker and member of the advisory board for Medicis/Valeant receiving honoraria; and was an investigator for Anacor, Astellas, Galderma, and LeoPharma receiving no compensation. Dr. Eichenfield was recused from discussions and voting on recommendations addressing moisturizers.

Wynnis L. Tom, MD served as an investigator for Anacor receiving no compensation.

Alfons Krol, MD served as an investigator for Pierre-Fabre receiving grants.

Amy S. Paller, MS, MD served as a consultant to Anacor, Galderma, LeoPharma, Promius, Sanofi/Regeneron, and TopMD receiving honoraria, and was an investigator for Astellas, Galderma, LeoPharma, and TopMD receiving no compensation.

James N. Bergman, MD served as a consultant for Pediapharm receiving honoraria. Dr. Bergman was recused from discussions and voting on recommendations addressing moisturizers.

Sarah L. Chamlin, MD, MSCI served on the advisory boards for Galderma, Valeant and Promius receiving honoraria. Dr. Chamlin was recused from discussions and voting on recommendations addressing moisturizers.

David E. Cohen, MD served on the advisory boards and as a consultant for Onset, Ferndale Labs and Galderma, receiving honoraria; served on the board of directors and as a consultant for Brickell Biotechnology and Topica receiving honoraria, stock and stock options; and was a consultant for Dermira and Dr. Tatoff receiving honoraria and stock options. Dr. Cohen was recused from discussions and voting on recommendations addressing moisturizers and topical steroids.

Kevin D. Cooper, MD served as a consultant for Kimberly Clark receiving salary. Dr. Cooper was recused from discussions and voting on recommendations addressing paper products.

Steven R. Feldman, MD, PhD, served on the advisory boards for Amgen, Doak, Galderma, Pfizer, Pharmaderm, Skin Medica, and Stiefel receiving honoraria; was a consultant for Abbott, Astellas, Caremark, Coria, Gerson Lehrman, Kikaku, Leo Pharma, Medicis, Merck, Merz, Novan, Peplin, and Pfizer receiving honoraria, and Celgene, HanAll, and Novartis receiving other financial benefits; was a speaker for Abbott, Amgen, Astellas, Centocor, Dermatology Foundation, Galderma, Leo Pharma, Novartis, Pharmaderm, Sanofi-Aventis, Stiefel, and Taro receiving honoraria; served as a stockholder and founder for Causa Technologies and Medical Quality Enhancement Corporation receiving stock; served as an investigator for Abbott, Amgen, Anacor, Astellas, Basilea, Celgene, Centocor, Galderma, Medicis, Skin Medica, and Steifel receiving grants, and Suncare Research receiving honoraria; and had other relationships with Informa, UptoDate, and Xlibris receiving royalty, and Medscape receiving honoraria. Dr. Feldman was recused from discussions and voting on recommendations addressing moisturizers.

Jon M. Hanifin, MD served on the advisory board for Chugai Pharma USA receiving honoraria; was a consultant for GlaxoSmithKline, Merck Elocon Advisory Board, Pfizer, and Valeant Elidel Advisory Board receiving honoraria; and served as an investigator for Asubio and Merck Sharp & Dohme receiving grants.

David J. Margolis, MD, PhD served as a principal investigator for a Valeant postmarketing study. All sponsored research income was paid directly to his employer.

Robert A. Silverman, MD served as a speaker for Galderma and Promius receiving honoraria. Dr. Silverman was recused from discussions and voting on recommendations addressing moisturizers.

Eric L. Simpson, MD served as a consultant for Asubio, Brickell Biotech, Galderma, Medicis, Panmira Pharmaceuticals, and Regeneron, and a speaker for Centocor and Galderma receiving honoraria; and was an investigator for Amgen, Celgene, Galderma and Regeneron receiving other financial benefits. Dr. Simpson was recused from discussions and voting on recommendations addressing moisturizers.

Craig A. Elmets, MD served on a data safety monitoring board for Astellas receiving honoraria.

Robert Sidbury, MD, Timothy M. Berger, MD, Kelly M. Cordoro, MD, Dawn M. Davis, MD, David J. Margolis, MD, PhD, Kathryn Schwarzenberger, MD, Hywel C. Williams, DSc, Julie Block, BA, Christopher G. Harrod, MS, and Wendy Smith Begolka, MBS, have no relevant relationships to disclose.