Efficacy and Safety Considerations in Topical Treatments for Atopic Dermatitis

Noreen Heer Nicol, MS, RN, FNP

Disclosures

Dermatology Nursing. 2010;22(3):2-11. 

In This Article

Treatment Strategies

As emphasized in clinical guidelines (Akdis et al., 2006; Eichenfield, 2004), proper daily skin care remains a cornerstone of AD treatment. Patients should receive detailed instructions on washing with appropriate cleansers and moisturizing with appropriate emollients. Cleansers that are mild, fragrance-free, dye-free, and pH-neutral should be used. Patients should be instructed not to scrub with a washcloth and to use warm water. Emollients such as ointments, creams, and lotions should be fragrance-free and contain minimal preservatives; they are most hydrating when used immediately after bathing. The judicious use of moisturizers can increase elasticity of the stratum corneum (Lebwohl & Herrmann, 2005) and improve overall epidermal barrier function (Loden, Andersson, & Lindberg, 1999), thereby making the skin less susceptible to irritants, allergens, and other triggers of flares. By supplying the stratum corneum with lipids to promote skin barrier repair, moisturizers may decrease the need for topical medications, including corticosteroids (Lebwohl & Herrmann, 2005). It is important to emphasize moisturizers should not be applied over or immediately before topical medications; otherwise, they may dilute or prevent penetration of medication into the skin.

Because of reduced epidermal barrier function, patients with AD have a higher risk of recurrent bacterial infections of the skin. Antibiotic treatment may be appropriate for these patients.

Topical Corticosteroids

Topical corticosteroids have been the predominant first-line treatment for moderate-to-severe AD for several decades. They are classified in seven potency groups based on cutaneous vasoconstriction tests, with the most potent in class I and the least potent in class VII. Ointments are more occlusive than creams, gels, lotions, or foams and are associated with a higher degree of systemic absorption compared with the other vehicles (Pariser, 2009). When devising an overall treatment strategy, the choice of which formulation to use depends on the site and severity of the flare as well as patient age and preference. As drug penetration is typically highest in thin skin areas of the body, such as eyelids and genitals (Pariser, 2009), only mild-to-moderately potent preparations of corticosteroids should be used in these areas. Low-potency topical corticosteroid preparations that contain other active ingredients, such as pramoxine, may also be safe and effective at relieving itch and inflammation in sensitive skin areas.

Adverse effects associated with topical corticosteroids are well documented. The higher the potency of the topical corticosteroid, the greater the risk for adverse effects. Long-term use of moderately potent preparations may cause thinning of the stratum corneum, thereby permitting entry of irritants and allergens that can perpetuate the cycle of irritation and inflammation in AD. Topical corticosteroids also inhibit collagen synthesis and can cause hypopigmentation, skin atrophy, rosacea, acne, and increased hair growth (Draelos, 2008). Systemic adverse effects associated with the long-term use of mid to mid-high potency preparations include adrenal suppression and growth suppression (Pariser, 2009).

To limit the risk of adverse effects, topical corticosteroid preparations should be used only as short-term or intermittent therapy and generally no more than twice daily. Low-potency corticosteroids are associated with fewer adverse effects than are those with higher potency. However, treatment strategy decisions should also balance the need for symptom relief, as insufficient potency also contributes to suboptimal control of AD symptoms.

Topical Calcineurin Inhibitors

Topical calcineurin inhibitors are effective nonsteroidal alternatives in the treatment of AD. Two topical calcineurin inhibitors are available: pimecrolimus cream (1%) and tacrolimus ointment (0.03% and 0.1%). As they do not cause skin atrophy, these nonsteroidal agents may be particularly useful in treating flares on the face, including perioral and periocular areas (Iskedjian, Piwko, Shear, Langley, & Einarson, 2004; Ong & Boguniewicz, 2008). Topical calcineurin inhibitors are associated with statistically significant improvements in AD patient and parent/caregiver quality of life outcomes (Boguniewicz et al., 2007).

Pimecrolimus is indicated as secondline therapy for the short-term and non-continuous chronic treatment of mild-to-moderate AD in non-immunocompromised adults and children 2 years of age and older who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable (Novartis Pharmaceuticals, 2009). Pimecrolimus demonstrated sustained efficacy in pediatric populations, as indicated by studies of up to 26 weeks (Langley et al., 2008). The use of pimecrolimus at the first signs of new exacerbations appears to prevent progression to major flares and prolongs the time to the first relapse (Gollnick et al., 2008). Pimecrolimus is effective in the long-term management of mild-to-moderate facial flares in children (Zuberbier & Brautigam, 2008) and adults, including eyelid dermatitis (Murrell et al., 2007). In a 12-week study investigating the treatment of facial AD in adults who were intolerant of or dependent on topical corticosteroids, pimecrolimus was associated with a significantly higher percentage of patients who became clear or almost clear of facial lesions compared with vehicle controls (46.5% vs. 16.2%, respectively) (Murrell et al., 2007). Similar efficacy results were obtained in a study of children ages 2–11 years with mild-to-moderate facial AD and dependence on or intolerance of topical corticosteroids, with statistically significant improvements in head and neck symptom severity and time to clearance (Hoeger et al., 2009). Pimecrolimus used at the first signs or symptoms of AD can eliminate or reduce the need for topical corticosteroids. In a 6-month study of adults with AD randomly given pimecrolimus 1% or vehicle cream, in the subgroup of patients with moderate AD, those who received pimecrolimus (n=62) averaged fewer days requiring corticosteroid treatment compared with those receiving vehicle (n=68) (9.5 ± 19.8 days vs. 37.0 ± 36.3 days, respectively) (Meurer et al., 2002). A mild transient burning sensation at the time of pimecrolimus application can occur, similar to the effect of tacrolimus 0.03% (Ellis et al., 2003).

Tacrolimus ointment, both 0.03% and 0.1% for adults and only 0.03% for children aged 2–15 years, is indicated as second-line therapy for the short-term and non-continuous chronic treatment of moderate-to-severe AD in non-immunocompromised adults and children who have failed to respond adequately to other topical prescription treatments for AD or when those treatments are not advisable (Astellas Pharma US, Inc., 2009). The anti-inflammatory efficacy of tacrolimus 0.1% is similar to a potent topical corticosteroid and is greater than mild topical corticosteroids such as hydrocortisone acetate 1% (Ashcroft, Dimmock, Garside, Stein, & Williams, 2005; Yan, Chen, Wang, Zhou, & Wang, 2008). A common adverse effect associated with tacrolimus is a burning or stinging sensation on the site of application, which is significantly greater than with topical corticosteroids (Rustin, 2007). Systemic absorption of tacrolimus appears to be minimal, indicating a lower risk of adverse events compared with corticosteroids (Undre, Moloney, Ahmadi, Stevenson, & Murphy, 2009). Low-dose intermittent, twice-weekly application of 0.1% tacrolimus has shown clinical potency in reducing the number and frequency of flares (Ehrchen, Sunderkötter, Luger, & Steinhoff, 2008).

Several years after the approval of pimecrolimus and tacrolimus, rare cases of lymphoma and skin malignancy have been reported following their use in children and adults. No causal relationship has been demonstrated; nevertheless, this has given rise to theoretical concerns about the safety of topical calcineurin inhibitors in the treatment of AD, which resulted in a black box warning associated with the drug (Astellas Pharma US, Inc., 2009; Fonacier et al., 2005; Novartis Pharmaceuticals, 2009). Several professional medical organizations have published statements asserting the available data show low systemic absorption and no associated increased risk of malignancy or immunosuppression (Fonacier et al., 2005; Ring et al., 2005). Recent studies of large patient populations found no increased risk of lymphoma (Arellano, Wentworth, Arana, Fernandez, & Paul, 2007). Surveillance is ongoing (Spergel & Leung, 2006).

Other Therapies

Although it is beyond the scope of this article to provide a comprehensive account of other therapies, they deserve a brief mention, to expand understanding of the array that may be used to treat AD. Systemic medications such as cyclosporine A may be used for severe, recalcitrant AD, although systemic adverse effects, including renal toxicity, are an enduring concern. Systemic corticosteroids are rarely indicated in the treatment of AD except for short courses while other treatment measures are being instituted. Some patients as well as physicians prefer systemic steroids to time-consuming skin care with hydration and topical therapy. However, the dramatic clinical improvement that may occur is frequently associated with severe rebound flaring of AD when steroids are discontinued (Nicol & Boguniewicz, 2008).

Wet-wrap therapy can be used on severely affected areas of dermatitis to increase hydration and absorption of topical therapy (Boguniewicz, Nicol, Kelsay, & Leung, 2008; Nicol, 1987). Ultraviolet light therapy can induce temporary remission of symptoms, but the lack of long-term, randomized, controlled data on the use of this treatment limits its clinical utility. Other experimental treatments include methotrexate, mycophenolate mofetil, azathioprine, and intravenous immunoglobulin (Ong, 2009; Ong & Boguniewicz, 2008).

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