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Oral Immunosuppressive Drugs in the Treatment of Atopic Dermatitis

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Oral Immunosuppressive Drugs in the Treatment of Atopic Dermatitis Oral immunosuppressive drugs in the treatment of atopic dermatitis IMPROVING PERFORMANCE AND SAFETY FLOOR M. GARRITSEN Colofon Oral immunosuppressive drugs in the treatment of atopic dermatitis Improving performance and safety Thesis with a summary in Dutch, Utrecht University, the Netherlands © Floor Garritsen, 2018 No part of this thesis may be reproduced, stored or transmitted, in any form or by any means, without prior permission of the author. ISBN: 978-90-393-6931-9 Cover design and layout: Die Jongens Printed and published by: Proefschriftmaken.nl Oral immunosuppressive drugs in the treatment of atopic dermatitis: improving performance and safety Orale immunosuppressiva bij de behandeling van constitutioneel eczeem: het verbeteren van effectiviteit en veiligheid (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 8 februari 2018 des middags te 2.30 uur door Floralie Maria Garritsen geboren op 22 oktober 1986 te Beek en Donk Promotor: Prof. dr. C.A.F.M. Bruijnzeel-Koomen Copromotoren: Dr. M.S. de Bruin-Weller Dr. M.P.H. van den Broek Table of contents Chapter 1 General introduction 7 Part I – Qualitative and quantitative exploration of oral immunosuppressive drug use in the Netherlands Chapter 2 Ten years experience with oral immunosuppressive treatment 23 in adult patients with atopic dermatitis in two academic centres Chapter 3 Use of oral immunosuppressive drugs in the treatment of atopic 39 dermatitis in the Netherlands Part II - Safety of long-term treatment with oral immunosuppressive drugs Chapter 4 Lymphopenia in atopic dermatitis patients treated 57 with oral immunosuppressive drugs Chapter 5 Risk of non-melanoma skin cancer in patients with 71 atopic dermatitis treated with oral immunosuppressive drugs Chapter 6 Is there an increased risk of cervical neoplasia in atopic 89 dermatitis patients treated with oral immunosuppressive drugs? Chapter 7 Pregnancy and fetal outcomes after paternal exposure to azathioprine, 99 methotrexate or mycophenolic acid: a critically appraised topic Part III - Optimizing the therapeutic potential of thiopurines Chapter 8 Thiopurine metabolite levels in patients with atopic dermatitis 123 and/or chronic hand/foot eczema treated with azathioprine Chapter 9 Improving outcome of azathioprine treatment in chronic eczema 141 by allopurinol co-prescription Chapter 10 First experience with thioguanine in the treatment 153 of patients with atopic dermatitis Chapter 11 General discussion 165 Chapter 12 Summary / Samenvatting 189 Appendices List of co-authors 204 List of publications 206 Acknowledgement 208 Curriculum vitae 212 1 General introduction 8 CHAPTER 1 Background Atopic dermatitis (AD, atopic eczema, eczema) is a chronic relapsing inflammatory skin disease, characterized by remissions and exacerbations. The prevalence varies between 2 and 5% in young adults and 20% in children, making it one of the most common skin diseases.1 It often occurs in families with other atopic diseases (bronchial asthma, allergic rhino conjunctivitis, food allergy).1,2 It is characterized by intense pruritus, excoriations and erythematous, xerotic, lichenified skin and has a characteristic age-dependent distribution pattern.1,3 AD and the increased risk of skin infections may have an effect on quality of life, sleep, self-esteem and systemic comorbidities, that may influence social contacts and activities, interpersonal relation- ships, participations in leisure and sports, and attendance or performance at school or work.4,5 Treatment of atopic dermatitis with oral immunosuppressive drugs A combination of emollients, topical corticosteroids, topical calcineurin inhibitors, oral antihista- mines and antibiotics, is often used in the management of AD.2 Different forms of phototherapy may also be effective.6-8 However, a subgroup of severe and difficult to treat patients remains. Patients in who AD is not controlled by topical treatment or UV-light treatment are candidates for oral immunosuppressive treatment. In addition, in patients who need daily treatment with potent topical corticosteroids of large body areas to control their AD, oral immunosuppres- sive drugs may be used to taper these corticosteroids to safe maintenance levels.1,2,9-12 Besides, sometimes side effects of the (intensive) treatment with topical corticosteroids, like striae and skin atrophy, are an indication for the start of oral immunosuppressive drugs. In some cases of difficult to treat AD patients the involved body surface may be limited, but the intensity of the eczema may still have huge impact on the quality of life. Examples are eyelid dermatitis and hand/foot eczema. Symptoms in these patients may be so severe and obstructive, that oral immunosuppressive treatment is indicated, although the eczema affects only a small part of the body service. All the above mentioned patients may be candidates for the treatment with oral immuno- suppressive drugs. In addition, recently, the expert panel of the international eczema council concluded that the decision to start systemic medication should include severity and quality of life assessments over time while considering the individual’s general health status, psycho- logical needs and personal attitudes towards systemic therapies.13 Oral immunosuppressive drugs that are used in the treatment of AD are systemic cortico- steroids, cyclosporine A, azathioprine, methotrexate, mycophenolate mofetil and enteric-coated mycophenolate sodium. Based on the mode of action (table 1), clinical efficacy during treat- ment with azathioprine, methotrexate and mycophenolate mofetil / enteric-coated mycopheno- late sodium can only be reached after 12-16 weeks; therefore these drugs are not suitable for treatment of acute exacerbations.1 GENERAL INTRODUCTION 9 Table 1 Mode of action of oral immunosuppressive drugs Drug Mode of action 1 Cyclosporine A11,14,15 - Acts primarily on T cells by inhibiting calcineurin and thus signal trans- duction mediated by T-cell receptor activation - Affects interleukin-2 production, B cells and dendritic cells - Can also suppress some growth-related pathways in keratinocytes Azathioprine11,16 - Purine synthesis inhibitor - Inhibits DNA synthesis and therefore affects active replicating cells, such as B cells and T cells Methotrexate11,16 - Antifolate metabolite - Affects the synthesis of DNA, RNA and purines - Negatively affects T-cell function, targeting several key T-cell functions Myfophenolate mofetil - Contains mycophenolic acid / enteric-coated myco- - Inhibits synthesis of DNA and RNA in B- and T-cell development by phenolate sodium11,14 inhibition of inosine monophosphate dehydrogenase and therefore prevents immune cell proliferation - Selectively affects B cells and T cells Clinical trials on oral immunosuppressive drugs Clinical efficacy and safety have been proven in clinical trials for most oral immunosuppres- sive drugs, including some head-to-head trials.17 Schmitt et al investigated the comparative efficacy of prednisolone and cyclosporine A for adults with severe eczema in a double-blind randomized multicenter trial.18 Patients were treated with prednisolone (initial dose 0.5-0.8mg/ kg daily) for two weeks followed by placebo for 4 weeks or cyclosporine A (2.7-4.0 mg/kg daily) for 6 weeks. They concluded that cyclosporine A was more efficacious than prednisolone, but the study was terminated early because of unexpected high numbers of withdrawals in the prednisone arm, mainly due to exacerbations of eczema. In the study of Haeck et al enteric- coated mycophenolate sodium and cyclosporine A were compared in an observer-blinded randomized controlled trial (RCT).14 Fifty-five patients with AD were treated with cyclosporine A (5mg/kg) for 6 weeks. Thereafter, patients received cyclosporine A (3mg/kg, n=26) or enter- ic-coated mycophenolate sodium (1440mg, n=24). Enteric-coated mycophenolate sodium was as effective as cyclosporine A as maintenance therapy in patients with AD, but clinical improve- ment with enteric-coated mycophenolate sodium was delayed compared to cyclosporine A. In addition, prednisone courses were often needed in the patients treated with enteric-coated mycophenolate sodium. In the study of Schram et al the efficacy and safety of methotrexate versus azathioprine was compared.16 In this RCT, 42 patients with severe AD were randomly assigned to receive methotrexate (10-22.5 mg/week) or azathioprine (1.5-2.5 mg/kg/day) for 12 weeks. Both treatments achieved clinically relevant improvement and were safe, but two (10%) patients in the methotrexate group and 4 (18%) patients in the azathioprine group required a prednisone course. This study clearly demonstrates the delayed mechanism of action of both methotrexate and azathioprine. 10 CHAPTER 1 Based on a systematic review performed by Roekevisch et al, including the above mentioned head-to-head trials and 31 other RCTs (12 different systemic treatments, total of 1653 patients), cyclosporine A is recommended as first-line treatment for short-term use.17 Azathioprine is recommended as second-line treatment option and methotrexate can be considered as a third- line treatment option. Oral immunosuppressive drugs in atopic dermatitis in daily practice The clinical trials with oral immunosuppressive drugs show encouraging results. However, a clinical trial setting is different
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