Topical Glucocorticoids

Glucocorticoids have been the cornerstone of antiinflammatory treatment for over 50 years. Because of potential side-effects, topical glucocorticoids are used primarily to control acute exacerbations of AD.

Patients should be carefully instructed in the use of topical glucocorticoids to avoid potential side-effects. The potent fluorinated glucocorticoids should be avoided on the face, the genitalia and the intertriginous areas. Patients should be instructed to apply topical glucocorticoids to their skin lesions and to use emollients over uninvolved skin. Failure of a patient to respond to topical glucocorticoids is often due to the inadequate amount applied. It is important to remember that it takes approximately 30 g of cream or ointment to cover the entire skin surface of an adult-sized patient for one application. The fingertip unit (FTU) has been proposed as a measure for applying topical corticosteroids and has been studied in children with AD. This is the amount of topical medication that extends from the tip to the first joint on the palmar aspect of the index finger. It takes approximately one FTU to cover the hand or groin, 2 FTUs for the face or foot, 3 FTUs for an arm, 6 FTUs for a leg, and 14 FTUs for the trunk. Of note, adequate application of topical corticosteroids has been shown to correlate with clinical improvement. Obtaining medications in larger quantities can result in significant savings for patients.

There are seven classes of topical glucocorticoids, ranked according to their potency based on vasoconstrictor assays from super-potent (class I) to low potent (class VII). Because of their potential side-effects, the super-potent and high-potent glucocorticoids should be used only for short periods of time and in areas that are lichenified, but not on the face or intertriginous areas. The goal is to use moisturizers to enhance skin hydration and lower-potency glucocorticoids or nonsteroidal agents for long-term therapy if needed. Side-effects from topical glucocorticoids are related to the potency ranking of the compound and the length of use as well as the area of the body to which the drug is applied, so it is incumbent on the clinician to balance the need for a more potent steroid with the potential for side-effects. In general, ointments have a greater potential to occlude the epidermis, resulting in enhanced systemic absorption compared to creams. Side-effects from topical glucocorticoids can be divided into local and systemic. Local side-effects include the development of striae and skin atrophy. Systemic side-effects in AD are uncommon unless high-potency steroids are used under occlusion, but adrenal suppression and cataracts have been reported. However, disease activity, rather than the use of topical corticosteroids, was shown to be responsible for low basal cortisol values in patients with severe AD. Of note, patients and caregivers continue to use topical corticosteroids suboptimally, primarily due to concerns about their use. This may include delaying application of the medication for a number of days after the start of a flare, which contributes to suboptimal outcomes. An expert consensus from the Dermatology Working Group pointed out that ‘in an ideal world, dermatologists, dermatology nurses, … practitioners, … pharmacists would work together to advise and reinforce information about the correct way to apply topical corticosteroids, and to address concerns about the safety of these highly effective agents. But in the real world, expert advice, even when given, is soon forgotten …’. Patients and caregivers need to have a basic understanding of topical corticosteroids, including their risks and benefits. Patients may erroneously assume that the potency of a topical corticosteroid is defined by the percent stated after the compound name (as discussed under ‘Education of Patients and Caregivers’ later in this chapter). At times, patients may be prescribed a high-potency corticosteroid with instructions to discontinue it within 7 to 14 days without a plan to step down, resulting in rebound flaring of their AD. Of note, only a few topical corticosteroids have been approved for use in very young children. These include desonide and fluticasone cream down to 3 months of age, alclometasone down to 1 year of age and mometasone down to 2 years of age. Indications are typically for up to 3 to 4 weeks.

Patients with AD are often labeled as topical corticosteroid treatment failures. Reasons for this may include inadequate potency of the preparation or insufficient amount dispensed or applied, S. aureus superinfection, steroid allergy and possibly corticosteroid insensitivity. A much more common reason for therapeutic failure is nonadherence to the treatment regimen. As with any chronic disease, patients or caregivers often expect quick and lasting benefits and become frustrated with the relapsing nature of AD. These factors need to be considered when faced with a patient not responding to therapy before considering alternative therapy, especially systemic treatment.

Topical Calcineurin Inhibitors

Since their approval by the FDA in 2000 and 2001, respectively, the topical calcineurin inhibitors (TCIs) – tacrolimus ointment (Protopic 0.03% and 0.1%) and pimecrolimus cream (Elidel 1%) – have become well-established, effective and safe nonsteroidal treatments for pediatric AD. They are currently indicated as second-line treatment for intermittent, noncontinuous use in children aged 2 years and older with moderate-severe AD (tacrolimus ointment 0.03%) and mild-moderate AD (pimecrolimus cream 1%). Tacrolimus ointment 0.1% is indicated for patients 16 years and older. Nevertheless, patients and caregivers frequently misunderstand their place in the treatment algorithm and have concerns about the boxed warning for these drugs. Of note, a Joint Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology reviewed the available data and concluded that the risk/benefit ratios of tacrolimus ointment and pimecrolimus cream are similar to those of most conventional therapies for the treatment of chronic relapsing eczema. In addition, a case-control study of a large database that identified a cohort of 293,253 patients with AD found no increased risk of lymphoma with the use of TCIs. Children may be prescribed TCIs to replace topical corticosteroids when they are not doing well or during a flare of AD, with unrealistic expectations for this class of drugs. Patients and caregivers may not be instructed about potential side-effects, a common reason for TCIs being discontinued, and patients labeled as treatment failures. While several studies have explored the use of TCIs in children under 2 years of age and as early intervention to reduce the incidence of flare and need for topical steroid rescue, they would currently be considered to be off-label therapy.

Proactive Therapy

As discussed in Chapter 50 , normal appearing skin in AD is not normal; there are immune and skin barrier abnormalities, as well as S. aureus colonization. In patients whose eczema tends to relapse in the same location, an approach that has gained increased attention is that of proactive therapy. After a period of stabilization, topical antiinflammatory therapy is instituted in areas of previously involved but normal-appearing skin, rather than waiting for a flare of eczema in a traditional reactive approach. Studies with topical corticosteroids and TCIs, including in pediatric patients, have shown clinical benefit with this approach. Of note, it is important to recognize that eczema first needs to be brought under control before a 2 to 3 times weekly, long-term regimen can be instituted. This approach would currently be considered off-label in the USA, but it has been approved in EU countries for children 2 years and older for up to 12 months with tacrolimus ointment and shown to be a cost-effective approach by the National Health Service of the UK.

Irritants

Patients with AD are more susceptible to irritants than are normal individuals. Thus it is important to identify and eliminate or minimize exposure to irritants such as soaps or detergents, chemicals, smoke, abrasive clothing and extremes of temperature and humidity. Alcohol and astringents found in toiletries can be drying. Cleansers, ideally formulated for sensitive skin, should be used in place of soaps, especially fragranced ones. Using a liquid rather than powder detergent and adding a second rinse cycle will facilitate removal of the detergent. Recommendations regarding environmental conditions should include temperature and humidity control to avoid problems related to heat, humidity and perspiration. Every attempt should be made to allow children to be as normally active as possible. Certain sports such as swimming may be better tolerated than others that involve intense perspiration, physical contact or heavy clothing and equipment, but chlorine should be rinsed off after swimming with the aid of a cleanser and the skin lubricated. Although ultraviolet light may be beneficial to some patients with AD, sunscreens should be used to avoid sunburn. Sunscreens formulated for the face are often better tolerated.

Specific Allergens

Potential allergens can be identified by taking a careful history and carrying out selective allergy tests. Negative skin tests or serum tests for allergen-specific immunoglobulin E (IgE) have a high predictive value for ruling out suspected allergens. Positive skin or in vitro tests, particularly to foods, often do not correlate with clinical symptoms and should be confirmed with controlled food challenges and, if indicated, trials of specific elimination diets. Avoidance of foods implicated in controlled challenges has been shown to result in clinical improvement. Infants who do not improve on formulas containing hydrolyzed proteins can be tried on amino acid formulas. However, these can add a significant financial burden for the family. Extensive elimination diets which, in some cases, can be nutritionally deficient, are rarely if ever required, because even with multiple positive allergy tests, the majority of children will react to three or fewer foods on controlled challenge. Unfortunately, patients with multiple positive allergy tests are often labeled as multiple food-allergic with no attempts to prove clinical relevance. Food challenges after getting the eczema under control and establishing a baseline for immediate, and less frequently delayed, reactions can be of immense value in managing the patient and helping the family with this stressful issue. It is noteworthy that in one retrospective study, 325 (89%) of 364 supervised oral food challenges were reported as negative. In addition, consultation with a dietitian familiar with food allergies can be extremely helpful to ensure a nutritionally sound diet for the child and suggest practical advice to caregivers. The Food Allergy Research & Education website ( www.foodallergy.org ) is a useful resource for patients and families with food allergy (see also Chapter 45 on food allergy).

In patients allergic to dust mites, prolonged avoidance of dust mites has been found to result in improvement of AD. Avoidance measures include: using dust mite-proof casings on pillows, mattresses and box springs; washing bedding in hot water weekly; removing bedroom carpeting; and decreasing indoor humidity levels with air conditioning. Because there are many triggers that can contribute to the flare of AD, attention should be focussed on identifying and controlling the flare factors that are important to the individual patient. In addition, allergic contact dermatitis may be overlooked in children and patch testing should be considered in children with AD (see Chapter 53 ). In a study to determine the frequency of positive and relevant patch tests in children referred for patch testing in North America, of the children with a relevant positive reaction, 34.0% had a diagnosis of AD.

Emotional Stressors

AD patients often respond to frustration, embarrassment and other stressful events with increased pruritus and scratching. In some instances, scratching is simply habitual; less commonly it is associated with secondary gain. Psychologic evaluation or counseling should be considered in patients who have difficulty with emotional triggers or psychologic problems contributing to difficulty in managing their disease. Relaxation, behavioral modification or biofeedback may be helpful in patients who habitually scratch.

Infectious Agents

Children with AD often are colonized or infected with various microbial organisms including bacteria, especially Staphylococcus aureus ( Figure 51-2 ), viruses including herpes simplex virus, and occasionally yeast or fungi. Methicillin-resistant S. aureus (MRSA) is becoming an increasingly important pathogen in patients with AD. Antistaphylococcal antibiotics are helpful in the treatment of patients who are heavily colonized or infected with S. aureus . Cephalosporins or penicillinase-resistant penicillins are usually beneficial for patients who are not colonized with resistant S. aureus strains. Erythromycin and other macrolide antibiotics are usually of limited utility due to increasing frequency of erythromycin-resistant S. aureus . Topical mupirocin is useful for the treatment of localized impetiginized lesions; however, in patients with extensive skin infection, a course of systemic antibiotics is more practical. Retapamulin ointment 1%, used twice daily for 5 days, was shown to be as effective as oral cephalexin twice daily for 10 days in the treatment of patients with secondarily infected dermatitis and was well tolerated. Use of topical neomycin, on the other hand, can result in development of allergic contact dermatitis because neomycin is among the more common allergens causing contact dermatitis. Treatment for nasal carriage with an intranasal antibiotic may lead to clinical improvement of AD. MRSA may require culture and sensitivity testing to assist in appropriate antibiotic selection. However, patients and caregivers need to be instructed that the best defense against microbes is an intact skin barrier, and basic skin care principles as discussed above should be emphasized. Of note, antiinflammatory therapy alone, with either a topical corticosteroid or topical calcineurin inhibitor, has been shown to improve AD and reduce S. aureus colonization of the skin.

Patient with atopic dermatitis who is secondarily infected with Staphylococcus aureus . Note multiple pustules and areas of crusting.

(From Weston WL, Morelli JG, Lane A, editors. Color textbook of pediatric dermatology. 3rd edn. St Louis: Mosby; 2002.)

Although antibacterial cleansers have been shown to be effective in reducing bacterial skin flora, they may be too irritating to use on inflamed skin in AD. Baths with dilute sodium hypochlorite (bleach) may also be of benefit to AD patients, especially those with recurrent MRSA as discussed above under ‘Hydration and Skin Barrier Protective Measures’, although they can be irritating. Of note, a single-center controlled study, while showing clinical benefit, did not demonstrate decreased skin colonization by S. aureus even with combined nasal treatment with mupirocin and after 3 months of treatment. A 2014 review discusses an approach to recurrent MRSA infections in patients with AD. Some studies have shown that silver-impregnated clothing reduced staphylococcal colonization, improved clinical parameters and reduced topical corticosteroid use in AD.

AD can be complicated by disseminated herpes simplex virus infection, resulting in Kaposi’s varicelliform eruption or eczema herpeticum ( Figure 51-3 ). Vesicular lesions are umbilicated, tend to crop, and often become hemorrhagic and crusted. These lesions may coalesce to large, denuded and bleeding areas that can extend over the entire body. Herpes simplex can provoke recurrent dermatitis and may be misdiagnosed as impetigo, although herpetic lesions can become superinfected by S. aureus . The presence of punched-out erosions, vesicles and/or infected skin lesions that fail to respond to oral antibiotics should initiate a search for herpes simplex. This can be diagnosed by a Giemsa-stained Tzanck smear of cells scraped from the vesicle base or by viral culture or polymerase chain reaction (PCR). Test results may be falsely negative if the samples are inadequate. Ideally, vesicle fluid should be obtained by unroofing one or more intact vesicles. Lumbar puncture should be considered if meningitis is suspected, but the presence of infected lesions over the lumbar areas should preclude this procedure. Ophthalmology consultation should be obtained for patients with periocular or suspected eye involvement. Treatment may be with oral acyclovir for less severe infections or intravenous acyclovir for widely disseminated disease or toxic-appearing patients at 30 mg/kg/day divided every 8 hours (for patients <1 year old) or 1,500 mg/m ² /day divided every 8 hours (for patients >1 year old) for 7 to 21 days, depending on the clinical course. Valacyclovir is indicated in pediatric patients 12 years or older for treatment of herpes labialis (2 g every 12 hours for 1 day) and patients 2 to <18 years of age for treatment of chickenpox (20 mg/kg 3 times daily for 5 days) up to a maximum dose of 1 g 3 times daily. Detailed instructions on preparing a liquid suspension (including shelf life) are available under ‘Extemporaneous Preparation of Oral Suspension’ in the manufacturer’s package insert. Of note, the suspension needs to be used within 4 weeks of being prepared. Acyclovir prophylaxis may be necessary for patients with recurrent eczema herpeticum.

Eczema herpeticum, the primary skin manifestation of herpes simplex in atopic dermatitis.

(From Fireman P, Slavin R, editors. Atlas of allergies. 2nd edn. London: Mosby-Wolfe; 1996.)

In patients with AD, smallpox vaccination, or even exposure to vaccinated individuals, may cause a severe widespread skin rash called eczema vaccinatum that is similar in appearance to eczema herpeticum. An increased risk of fatalities resulting from eczema vaccinatum has been reported in AD. Even if not fatal, eczema vaccinatum is often associated with severe scarring and lifelong complications following recovery from this illness.

Fungi may play a role in chronic inflammation of AD. There has been particular interest in the role of Malassezia (Pityrosporum) in AD. Malassezia sympodialis is a lipophilic yeast commonly present in the seborrheic areas of the skin. IgE antibodies against M. sympodialis are found in AD patients, most frequently in patients with a head and neck distribution of dermatitis. The potential importance of M. sympodialis as well as other dermatophyte infections is further supported by the reduction of AD skin severity in patients treated with antifungal agents. However, even patients with IgE antibodies to M. sympodialis often respond better to topical steroids than to topical antifungal therapy, and systemic antifungal therapy may benefit AD patients through antiinflammatory properties.

Control of Pruritus and Sleep Disturbance

The treatment of pruritus in AD should be directed primarily at the underlying causes. Reduction of skin inflammation and dryness with topical glucocorticoids and skin hydration, respectively, will often symptomatically reduce pruritus. Inhaled and ingested allergens should be eliminated if documented to contribute to eczema. Systemic antihistamines act primarily by blocking the H ₁ receptors in the dermis and thereby ameliorating histamine-induced pruritus. However, histamine is only one of many mediators that can induce pruritus of the skin, minimizing benefit from antihistamine therapy. Some antihistamines have anxiolytic agents and may offer symptomatic relief through their tranquilizing and sedative effects. Studies of newer nonsedating antihistamines have shown variable results in the effectiveness of controlling pruritus in AD patients although they may be useful in the subset of AD patients with concomitant urticaria. Because pruritus is usually worse at night, sedating antihistamines such as hydroxyzine or diphenhydramine may offer an advantage with their soporific side-effects when used at bedtime. Doxepin hydrochloride has both tricyclic antidepressant and H ₁ – and H ₂ -histamine receptor blocking effects. Thus, it may be useful in treating children and adolescents who do not respond to H ₁ sedating antihistamines. If nocturnal pruritus remains severe, short-term use of a sedative to allow adequate rest may be appropriate. Treatment of AD with topical antihistamines or topical anesthetics is not recommended because of potential cutaneous sensitization. Other treatment options for sleep disturbance used by the behavioral health clinicians in the AD program at National Jewish Health include clonidine and melatonin.