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Department of Dermatology
Hospital de la Santa Creu i Sant Pau
Atopic dermatitis (AD) is a chronic inflammatory cutaneous disease with a high prevalence in childhood.(1) It involves pruritus and eczematous lesions in patients with hypersensitivity to environmental factors. Irritation predisposes to scratching and increases susceptibility to acquired secondary infections (bacterial, fungal or viral). Staphylococcus aureus involvement has been suggested in a study reporting that antistaphylococcal systemic treatment reduces clinical severity of skin lesions. AD is commonly associated with asthma and allergic rhinitis.
Treatment of AD includes general measures to maintain skin barrier function by means of hydration and avoidance of irritants or allergen factors. Patient and family education is therefore an important aspect.
Pharmacological treatment is based on topical corticosteroids and/or topical calcineurin inhibitors (TCIs). Systemic corticosteroids, phototherapy, ciclosporin or azathioprine may be needed in severe refractory disease. The use of interferon gamma, methotrexate, leukotriene antagonists and biological agents has been reported. This article discusses recent advances in the topical treatment of AD.
Topical corticosteroids are the mainstay of pharmacological treatment for AD.(2) These agents have vasoconstrictor, anti-inflammatory, antiproliferative and immunosuppressor effects. Corticosteroids act through different mechanisms of action and exert effects on various cells.(3) They may therefore be associated with numerous local and systemic side-effects, including skin atrophy, striae, telangiectases, acneiform reaction, contact dermatitis and hypothalamic/ pituitary/adrenal axis suppression.(4) These effects are related to drug potency, long-term treatment, localisation and extension of disease. The vehicle influences the corticosteroid potency. Recent publications have investigated the advantages of foam over traditional vehicles.(5) The alcohols used in the foam increase penetration and change the properties of the stratum corneum, allowing delivery of the drug through the intracellular pathway. Conventional vehicles require hydration of the intercellular spaces prior to effective delivery of the drug (intercellular pathway). The misuse and overestimation of the real risks associated with corticosteroids has led to a steroid phobia while simultaneously motivating the investigation of new topical therapies.
Topical calcineurin inhibitors
TCIs are a new class of nonsteroid immunomodulators that bind to the cytosolic protein macrophilin-12. This combination creates a complex, FK-506, that inhibits calcineurin activity and thereby lymphocyte T activation. The mechanism of action of TCIs is more selective than corticosteroids and primarily involves T-cells.(6–8) The most common side-effects are a burning sensation and pruritus. Such effects are transient, appearing mainly with the first applications. Cases of flushing after alcohol ingestion have been described.(9) It has been reported that TCIs might increase the risk of skin cancer, as they could encumber repair of DNA damage produced after sun exposure.(10) However, more recent publications have found no evidence of increased risk of skin cancer or lymphoma.(11,12) Systemic absorption is limited and insufficient to cause systemic immunosuppression.
There are presently two commercialised products: tacrolimus ointment and pimecrolimus cream.
Tacrolimus has been studied in short- and long-term trials in both child and adult patients with moderate to severe disease.(13–19) Reports concluded that it was more effective than vehicle and cortico‑steroids.(20–22) Pimecrolimus has been studied in short- and long-term trials, mainly in children with moderate disease,(23–28) where it has been found to be more effective than vehicle but less effective than corticosteroids.(29) In addition, a recent study that compared tacrolimus versus pimecrolimus in children with moderate or severe AD concluded that tacrolimus was superior to pimecrolimus.(30,31)
Other treatments in AD
As leukotrienes play a role in the inflammatory mechanism of AD, some studies have postulated that leukotriene antagonists are useful in the treatment of this disorder.(32–34) However, since this has not been confirmed in recent publications concerning montelukast,(35) further studies are needed to clarify these findings. Several recent studies have investigated the skin barrier composition, particularly the lipids of the stratum corneum and their role in transepidermal water loss. Prior to such research, standard emollients were composed of nonphysiological lipids. They acted by forming occlusive layers over the skin.(36) Physiological lipids (ceramides, cholesterol and free fatty acids) compose new emollients and moisturizers capable of crossing the stratum corneum, penetrating the keratinocytes and mixing with endogenous lipids. Once they enter the interstitial space, they help maintain skin hydration and regulate the inflammatory component.(37–39) Finally, combination therapy,(40) applied concomitantly(41) or sequentially,(42) has proven effective. The use of drugs with different mechanisms of action may allow a reduction in dosage and side-effects. Recent studies have confirmed the superiority of combination therapy, either concomitant or sequential, as compared with corticoid or TCI monotherapy.(43) More rigorous controlled clinical trials are needed to clarify optimal dosages and combinations.
The treatment of AD covers a broad spectrum of therapeutic measures, which include daily skincare with moisturizers and emollients, avoidance of irritants or allergen factors, and topical or systemic pharmacological agents. These measures should be individualised for each patient.
Since AD is a chronic disease, we should take the different therapeutic strategies into consideration and optimise the diverse treatment options. Corticosteroids continue to be first-line therapy in inflammatory diseases such as AD, but they must be used with caution to avoid side-effects and patient concern.
According to the latest guidelines for AD, the recommended treatment for flares appears to be high-potency corticosteroids for no longer than two weeks. After this period, it is recommended to apply medium- or low-potency corticosteroids, TCIs or a combination of the two as maintenance. TCIs can also be used as first-line treatment, with proven efficacy in flares, especially in sensitive locations (face, groins, armpits) or when the condition is widespread. Long-term TCIs treatment is presently being investigated in several ongoing studies. Nevertheless, further controlled clinical trials are needed to clarify dosage and timing of therapeutic protocols in combined therapy.