Download with Tacrolimus Clinical Experience Ointment in Atopic Dermatitis III

Clinical Experience with Tacrolimus III Ointment in Atopic Dermatitis 8

Clinical Experience in Adults S. Reitamo

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Clinical Experience in Children Y. de Prost

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The Role of Tacrolimus Ointment in Atopic Dermatitis S. Reitamo

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Other Potential Dermatological Indications for Tacrolimus T. Assmann, T. Ruzicka

8 Clinical Experience in Adults S. Reitamo

a000000000 Introduction The goal of therapy for atopic dermatitis should be a treatment that is well tolerated and can be used without significant side effects to achieve complete, long-term control. Atopic dermatitis is a “hot topic” in contemporary dermatology because the management techniques available to date have failed to achieve the goal of adequate disease and symptom control. The traditional approach, employing preventive life style and environmental measures, general skin care and emollients, has not been sufficiently effective to control and prevent disease exacerbations continuing in many patients. Furthermore, the reactive use of topical corticosteroids controls atopic dermatitis successfully in some, but by no means in all cases, and then only with careful adherence to a management routine that many patients find time consuming [11]. Atopic dermatitis is a chronic condition that significantly impairs the lives of adult patients. Their quality of life is compromised not only by physical discomfort and the social and psychological sequelae of disfigurement, but also by the exacting lifestyle modifications that many individuals need to undertake to achieve reasonable symptomatic control. Symptomatically, atopic dermatitis in adults may affect any region of the body, although skin flexures are particularly vulnerable, and there is also significant incidence of chronic hand dermatitis, which may impact seriously on employment [14]. Face and neck dermatitis are particularly problematic, due to both their visibility and the sensitivity of the skin in these areas to corticosteroids. Atopic dermatitis in many patients is of moderate severity with a relapsing and remitting course, but in 2% of patients symptoms occasionally become more severe, with large areas of the body affected [11]. Treatment with topical corticosteroids is central to the problem of effective disease management. The most important weakness of corticosteroids is that they cannot be used for extended periods without problematic side effects, of which skin atrophy is the most notorious and important (Fig. 8.1) [6, 11, 17]. Consequently, these agents can be used on any given area of skin for only a limited duration. Subsidiary but related problems with corticosteroids are disease rebound after discontinuation and tachyphylaxis, a decrease in clinical efficacy over time that requires the use of more potent agents to achieve the same therapeutic effect. These events fur-

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8 Clinical Experience in Adults

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Figure 8.1. Atrophy of the face with multiple teleangiectasies (a) and striae (b) after long-term use of midpotent topical corticosteroids in a 45-year-old female patient with severe atopic dermatitis

This new tacrolimus treatment concept is revolutionising the management of atopic dermatitis

ther complicate the use of topical corticosteroids and make the task of achieving a balance between efficacy and tolerability a challenge for many patients in general clinical practice. Many cases of atopic dermatitis are thus poorly controlled within the steroidbased treatment paradigm. Poor compliance with treatment, corticosteroid phobia, a failure to use corticosteroids as directed and the risk for disease rebound are all likely to contribute to undertreatment of symptomatic atopic dermatitis, while conversely some patients suffer from side effects associated with excessive steroid use. Tacrolimus ointment (Protopic®; Fujisawa), a novel steroid-free topical immunomodulator, promises to overcome these problems. It offers the prospect of a treatment that is as effective as mid-potent to potent corticosteroids in the short-term management of atopic dermatitis symptoms but can be used safely for intermittent long-term treatment without the risk of corticosteroid-associated side effects. This enables patients to simplify their treatment regimen, using emollients if necessary, and using tacrolimus ointment monotherapy from the first sign of an inflammatory exacerbation or pruritus up until complete resolution, thus avoiding an unnecessary delay in treatment. Furthermore, there is no need for patients to consider switching between different agents, or ceasing treatment before complete healing is achieved, due to fear of adverse effects. This new tacrolimus treatment concept is revolutionising the management of atopic dermatitis. The clinical profile of tacrolimus oint-

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Early Clinical Development

ment in the management of adult atopic dermatitis has now been described in detail in an extensive programme of clinical studies, the results of which are the subject of this chapter.

a000000000 Early Clinical Development Tacrolimus was first investigated in the context of atopic dermatitis in the early to mid-1990s [12, 18]. Prior to investigation in large-scale clinical trials, a number of small studies indicated that tacrolimus ointment was a safe and effective treatment for atopic dermatitis, and established the parameters of its use [3]. For further details on the development of tacrolimus, please refer to the chapter by Goto (Chap. 5) in this volume.

Drug Concentration Studies Drug concentration studies determined the most suitable strengths of tacrolimus ointment for subsequent clinical development. The key study was a large, parallelgroup, fixed-dose study conducted in Europe [28]. In this study, adult patients with moderate to severe atopic dermatitis were randomly assigned to receive either vehicle (n=54) or one of three strengths of tacrolimus: 0.03% (n=54), 0.1% (n=54) or 0.3% (n=51). Treatment was applied twice daily to a symptomatic area of skin of up to 1000 cm² in size, approximately 10% of the body surface area (BSA) affected, for 3 weeks. All three concentrations of tacrolimus were associated with a clinically and statistically significant improvement in the severity of atopic dermatitis compared with the vehicle group (p