SummaryAtopic eczema (or atopic dermatitis) is the most common chronic skin disease in childhood, and it can have a significant impact on the lives of patients and their families. New and effective treatments have been introduced in recent years, and it has been postulated that good control of atopic eczema with these agents may also reduce the incidence and severity of asthma.
Atopic eczema (or atopic dermatitis) is the most common chronic skin disease in childhood, and it can have a significant impact on the lives of patients and their families. New and effective treatments have been introduced in recent years, and it has been postulated that good control of atopic eczema with these agents may also reduce the incidence and severity of asthma. The role of the immune system in atopic dermatitis has long been recognised, ever since the term ‘atopy’ was introduced in relationship to atopic eczema, asthma and ‘hay fever’ over 80 years ago. Current therapy for atopic eczema is aimed at hydration of the skin, reduction of inflammation and relief of symptoms such as pruritus.
Since the 1950s, topical corticosteroids have been the mainstay of treatment for atopic eczema. In 1953, Sulzberger and colleagues introduced the first topical steroid (hydrocortisone) into clinical practice and thereby revolutionised the treatment of atopic eczema. Alterations to this basic molecular structure have led to the development of more potent topical steroids, but with the disadvantage of an increased potential for adverse events.
The adverse events associated with topical steroid use, including skin atrophy, striae, telangiectases, acneform eruptions and the risk of absorption leading to systemic effects such as adrenal-axis suppression, have been a major concern for many physicians, patients and parents, and have been the major driving force behind the search for alternative treatments for atopic eczema. Tacrolimus and pimecrolimus, which are non-steroidal topical immunomodulators, have a distinct pharmacological mechanism from corticosteroids – not involving collagen synthesis nor causing vasoconstriction – and therefore eliminate the concerns of skin atrophy.
Tacrolimus is a macrolide produced by Streptomyces tsukabaensis, a bacterium found in the soil near . Its name is derived from Tsukuba (the location of its discovery), macrolide (its chemical class), and immune suppression (its primary activity in humans). Tacrolimus was first discovered in 1984 after the utility of systemic ciclosporin A – a potent inhibitor of T cells – was noted in the treatment of atopic eczema and psoriasis. Administered orally, ciclosporin A has a risk of serious systemic effects, particularly renal toxicity. Ciclosporin A has little activity in a topical formulation due to its large molecular size, which impedes its ability to penetrate the skin. Tacrolimus, previously known as FK506, has also been used intravenously and orally for the prevention of organ rejection after transplantation. Whilst not structurally related, the mechanism of action of tacrolimus closely resembles that of ciclosporin A. Through inhibition of calcineurin, these compounds are able to inhibit the production of proinflammatory cytokines by T cells.
Topical tacrolimus represented the first agent in a new class of topical immunomodulators, called ‘TIMs’. However, it surely is not the first topical immunomodulator, as corticosteroids share the same immunomodulating effects, although they have never been referred to as such. Tacrolimus, and the newer non-steroid topical immunomodulator, pimecrolimus, should therefore be more appropriately referred to as topical calcineurin inhibitors or TCIs.
Topical calcineurin inhibitors certainly have filled a role where topical corticosteroid monotherapy has been suboptimal, particularly in the longer-term maintenance therapy of atopic eczema and when treating areas of thin skin and occluded anatomic locations such as the face, neck and intertriginous areas. As summarised in the tacrolimus review that is featured in this issue of Drugs in Context, the efficacy and safety of tacrolimus has been demonstrated across a broad collection of clinical studies. Whilst the majority of these trials have evaluated topical calcineurin inhibitors as monotherapy, ongoing studies are aimed at defining optimal combination therapy along with topical corticosteroids, in order to maximise the efficacy of each agent whilst minimising the risk of adverse events. This, along with the evidence supporting early intervention to interrupt the atopic march, will likely shift the paradigm for treatment of atopic eczema in the future.
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This Editorial has been written by the specialist opinion leaders Brandie J Roberts, Fellow, Pediatric and Adolescent Dermatology Children’s Hospital and Health Center and University of California, San Diego, San Diego, California, US and Lawrence F Eichenfield Chief, Pediatric and Adolescent Dermatology, Professor of Pediatrics and Medicine (Dermatology) Children’s Hospital and Health Center and University of California, San Diego, San Diego, California, US and published in the latest issue of the serial publication, Drugs in Context.
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