Citation for published version (APA): Christoffers, W. (2014). Hand eczema: interventions & contact allergies [S.l.]: [S.n.]

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1 University of Groningen Hand eczema Christoffers, Wianda IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2014 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Christoffers, W. (2014). Hand eczema: interventions & contact allergies [S.l.]: [S.n.] Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Summary Hand eczema: interventions & contact allergies Wietske Andrea Christoffers Department of Dermatology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands 241

3 Summary This thesis contains a series of review articles and clinical studies on hand eczema and allergic contact dermatitis. A general introduction of hand eczema is presented in chapter 1, with additional focus on allergic contact dermatitis. Hand eczema is a common skin condition with prevalence up to 10%. The etiology of hand eczema is often multifactorial, although atopic dermatitis and wet work are well-known risk factors. Chapter 1 describes the diagnostic steps to establish hand eczema in daily practice and discusses the risk factors, etiology and consequences of hand eczema. Moreover the objectives of this thesis are presented. Primary objective of this thesis is to provide physicians more insight in the treatment of hand eczema. In chapter 2 we present a part of the Cochrane review on different interventions for hand eczema. The original Cochrane review included 55 randomized controlled trials with a total of 4,619 participants. The review covered a wide variety of different interventions: emollients, topical corticosteroids, phototherapy, topical calcineurin inhibitors, systemic interventions and some rather unconventional treatments. Most studies used a placebo and only five studies compared two different classes of interventions. The studies had substantial clinical heterogeneity in interventions, outcome measures and duration. Statistical pooling was not possible for the majority of the studies, because they were considered too heterogeneous. For each study the risk of bias was weighted according to the Cochrane Hand Book Guidelines. Many studies were at unclear risk of bias in one or more components of trial design, however the quality of studies and reporting improved over time. The results of this review cannot be used to inform clinical practice with regard to the best way of managing hand eczema due to the diversity and quality of the included studies and the lack of comparing studies. Topical corticosteroids and phototherapy appear to be the major standard treatment modalities. However, there is little evidence of a comparative advantage of one specific treatment within these categories, and also little evidence for a comparative advantage over other treatment modalities: further studies are needed. In this thesis only the conventional systemic interventions are presented. We included seven studies with a total of 1,661 participants investigating different interventions: alitretinoin (n = 3), acitretin (n = 1), cyclosporine (n = 1), azathioprine (n = 1) and one study comparing cyclosporine to alitretinoin. In general, the studies on systemic interventions were well conducted, with few biases in trial design, except from sponsoring by pharmaceutical companies. Alitretinoin was effective in the treatment of chronic hand eczema in well-conducted randomized controlled trials with large numbers of patients (n = 1,468). However, since the only study that compared alitretinoin to another treatment modality (cyclosporine) was ended prematurely and no other comparisons were conducted, the superiority of alitretinoin over other treatment modalities remains unclear. 242

4 In chapter 3 we discussed questions physicians encounter during daily-practice from an evidence-based perspective. Overall, insufficient evidence was found to base a choice between short bursts of potent topical corticosteroids compared with continuous application of mild corticosteroids, systemic therapy as maintenance therapy, iontophoresis, additive effect of topical antibacterial agents and topical calcineurin inhibitors. Little evidence was found for the steroid-sparing effect of emollients, although these are widely prescribed. With regards to phototherapy both PUVA and UVB are effective, although there is no evidence of a clinical advantage of one modality over the other. Oral retinoids, especially alitretinoin, are effective and well tolerated in hand eczema, especially in hyperkeratotic hand eczema. With regards to education for secondary and tertiary prevention: these seemed to be effective; however, long-term data are needed. Cyclosporine is used off-label to treat hand eczema. In chapter 4 we retrospectively studied the effectiveness of cyclosporine in a daily practice cohort of 102 patients with chronic hand eczema. Drug survival and a clustered Physician Global Assessment (PGA) were used to study the effectiveness of treatment with cyclosporine in patients at two Dutch Dermatology Departments. The median drug survival rate was 10.3 months. The overall drug survival rates after 6 months, 1, 2 and 3 years were 61.7%, 45.2%, 18.6% and 13.9%, respectively. Main reasons for discontinuation were adverse events, mainly early in treatment, and ineffectiveness. After three months a good response to treatment was recorded in 59.8% of the patients. In the subgroup of patients with recurrent vesicular hand eczema cyclosporine was especially effective: 66.7% achieved a PGA1 (more than 50% improvement compared to the baseline) score after three months of treatment and the overall drug survival was borderline significant longer than in other groups. Based on this study we would like to recommend cyclosporine as valuable treatment option for patients with hand eczema, especially in patients with recurrent vesicular hand eczema. Moreover, cyclosporine might be used for longer periods of time instead of short pulses of three months. The etiology of hand eczema is multifactorial and sometimes unclear, but allergic contact dermatitis is a well known cause. The most common sensitizations among 1,571 hand eczema patients are discussed in chapter 5. Moreover the relation between specific contact allergens and clinical subtypes of hand eczema according to the guidelines of the Danish Contact Dermatitis Group (DCDG) was studied. The most frequently found clinical subtypes were recurrent vesicular hand eczema (39.7%), chronic fissured hand eczema (35.5%), hyperkeratotic palmar eczema (7.6%) and pulpitis (4.0%). Subjects with recurrent vesicular hand eczema were significantly more likely to be sensitized (OR 1.55, p<0.001), whereas subjects with hyperkeratotic palmar eczema and pulpitis were less likely to be sensitized (OR 0.51, p<0.001; OR 0.44, p = 0.003). In addition females and patients over the age of 40 were more likely to be sensitized. Overall, metals (nickel sulphate, cobalt chloride), fragrances and 243

5 preservatives (methylchloroisothiazoline/ methylisothiazoline, methyldibromoglutaronitrile) were the most frequent sensitizers in patients with hand eczema. This did not deviate in the different clinical subtypes, although subjects with recurrent vesicular hand eczema were significantly more frequently sensitized to nickel sulphate (OR 1.50, p = 0.002) and other allergens compared to other clinical subtypes of hand eczema. Therefore, we concluded that in the diagnostic work up of hand eczema subjects with recurrent vesicular hand eczema should be patch tested, especially women of older age. However, the need for patch testing males with hyperkeratotic palmar eczema is less imperative. Allergic contact dermatitis can be very severe and may result in absence from work or change of occupation, as was demonstrated in chapter 6. Herein we discussed a process operator that suffered from a severe occupational-related bullous allergic contact dermatitis due to various acrylates. In this case report 1,6-hexanediole diacrylate (HDDA) and glycidyl methacrylate (GMA) were the main culprits, alongside various other acrylates. The importance of patch testing with a dilution series of acrylates to distinguish between a contact allergy and an irritant reaction was emphasized. Moreover, the importance of investigating the products used at work by a patient and testing the purity of these products was highlighted. The need to consider allergens which are not included in a standard patch test series was also emphasized in chapter 7. Here we studied a process operator which was sensitized to isobornyl acrylate. We tried to establish whether isobornyl acrylate was an underdiagnosed allergen. However, besides the process operator and an incidental case report, no other cases of isobornyl acrylate contact allergy were recorded: neither in literature, nor in our cohort of acrylate-sensitized patients which were re-patch tested with isobornyl acrylate. In addition, the results of our (meth)acrylate patch test series over the last two decades were studied. A total of 151 patients was patch tested; 24 had positive reactions. The most frequent sensitizers were: 2-hydroxypropyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl methacrylate, and diethyleneglycol diacrylate. Because of the risk of active sensitization, the (meth) acrylate patch test series should only be patch tested on indication. To minimize the exposure to acrylates, we composed a hypothetical screening series. Screening with 2-hydroxypropyl acrylate, ethyleneglycol dimethacrylate, ethoxylated bisphenol A glycol dimethacrylate and trimethylolpropane triacrylate identified 91.7% of our patients that were sensitized to (meth)acrylates. Since hand eczema is a chronic, often relapsing condition, patients might be inclined to search alternative treatments as was demonstrated in chapter 2. Another example of alternative treatments is tea tree oil, an oil distilled from the Melaleuca alternifolia. Aside from a natural remedy, tree tea oil is also a popular ingredient in household and cosmetic products. Oxidation of tea tree oil results in degradation products, such as the endoper- 244

6 oxidase ascaridole, which can cause allergic contact dermatitis. In chapter 8 we presented two cases of allergic contact dermatitis due to oxidized tea tree oil and ascaridole. In chapter 9 we aimed to identify the optimal patch test concentration for ascaridole, and to investigate the relationship between a positive reaction to ascaridole and a positive reaction to oxidized tea tree oil in 319 (hand) eczema patients. With an increasing ascaridole test concentration, the frequency of positive reactions increased: ascaridole 1% caused positive reactions in 1.4% of our patients; ascaridole 2% in 5.5%; and ascaridole 5% in 7.2%. However, the frequencies of irritant and doubtful reactions also increased with an increase in concentration. Therefore we recommended patch testing ascaridole at 2% in petrolatum. Every positive reaction to oxidized tea tree oil was accompanied by a positive reaction to ascaridole, but not every positive reaction to ascaridole was accompanied by a positive reaction to tree tea oil. Some clinical relevant reactions were missed by patch testing tea tree oil only. Thus patch testing distinct components such as ascaridole, should be preferred over patch testing complex mixtures, such as oxidized tea tree oil. In chapter 10 we gave a general discussion on this thesis and the main findings. All these findings were combined into a flowchart which provides the physician insight in the treatment of different clinical subtypes of hand eczema. Guidance, education and emollients are the basic of hand eczema management. Topical corticosteroids are the mainstream treatment. In patients with chronic hand eczema, unresponsive to topical corticosteroids, alitretinoin is highly recommended. However, in patients with the clinical subtype recurrent vesicular hand eczema, cyclosporine can be considered as first line systemic treatment. To further confirm our treatment algorithm, we provided suggestions for future studies. 245

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