In vivo evaluation of therapeutic options in atopic dermatitis

Abstract

Atopic dermatitis (AD, or atopic eczema) is an inflammatory itchy skin disease. AD patients often have high serum immunoglobulin E (IgE) levels, T-cell activation and eosinophilia in peripheral blood. The dermal infiltrate of AD contains mainly T-cells, eosinophils and dendritic cells. Epicutaneous patch tests with aeroallergen application for 24-48 h can induce eczematous lesions in sensitized patients with AD. This is named the atopy patch test (APT). The APT is used as in vivo research model to study the mechanisms involved in the induction of eczema by inhalant allergens. AD treatment consists of application of emollients and topical corticosteroids. Other topical treatment strategies are the relatively new topical calcineurin inhibitors, tacrolimus and pimecrolimus. For more severe forms of AD, local phototherapy can be prescribed, but also oral use of ciclosporin A, corticosteroids, azathioprine and mycophenolate mofetil. The overall aim of this thesis was to evaluate several therapeutic options for AD patients. We have focussed on two different systems to determine clinical efficacy 1) improvement of lesional, active AD skin and 2) inhibition of the APT as in vivo provocation model for allergic inflammation in AD. In chapter 2, medium-dose ultraviolet (UV) A1 (340-400 nm) was compared with narrow-band UVB (311 nm) phototherapy. We demonstrate that both treatment modalities are clinically equal effective. This is supported by a decrease in inflammatory cell infiltrate in both treatment groups. Based on practical advantages of NB UVB, as well as patient-friendliness, which are less heat load and shorter duration of phototherapy, the preferred choice of phototherapy for AD should be NB UVB. In chapter 3, the clinical effect of the newly developed drug mepolizumab, which is a monoclonal antibody to interleukin 5 (IL-5) aimed at eosinophil depletion, is investigated. We conclude that short-term intravenously administered treatment with mepolizumab has no clinical effect in AD patients, despite a significant decrease in peripheral blood eosinophils. Moreover, in chapter 5 we observe no inhibitory effect on the APT after mepolizumab therapy. So, despite a reduction of blood eosinophils, remaining blood eosinophils are able to migrate into the skin. Future studies are necessary to investigate if prolonged anti-IL-5 therapy (> 3 months) results in a more rigorous depletion of blood eosinophils and consequently in a decrease of tissue eosinophils. In chapter 4, two frequently used APT methods were compared. It was concluded that both APT methods can be used as in vivo model to study the initiation of allergic inflammation in AD. In chapter 6 the influence of pretreatment with topical tacrolimus 0.1% on the APT was studied and compared with pretreatment with a topical corticosteroid and with placebo. Tacrolimus was not capable to inhibit the APT reaction, in contrast to the suppressive effect of pretreatment with topical corticosteroids. This suggests that preventive treatment of non-lesional skin with tacrolimus will not be effective in AD, in contrast to topical corticosteroids.