Clinical dermatology • Review article
What’s new in atopic eczema? An analysis of systematic reviews published in 2009–2010
A similar and more detailed review to the material published here appeared in the 2010 Annual Evidence Update on Atopic Eczema published by NHS Evidence – skin disorders in September 2010 (http://www.library.nhs.uk/skin/ViewResource.aspx?resID=386959&tabID=289&catID=8310), and explicit reference is given to that fuller version throughout. There are no copyright issues with using material from that source.
Conflict of interest: KS, DJCG and HCW work in the UK National Health Service (NHS). NHS Evidence – skin disorders is funded by the NHS. DJCG and HCW have no financial connections with any pharmaceutical company. KS has previously received funding by Almirall and Janssen for travel/accommodation to attend courses.
Professor Hywel Williams, Centre of Evidence Based Dermatology, University of Nottingham, Queen’s Medical Centre, Nottingham, NG7 2UH, UK
This review provides a summary of key findings from 18 systematic reviews on atopic eczema, published or indexed between January 2009 and 24 August 2010. There was no good evidence on the possible benefit of organic food consumption and eczema. Maternal intake of fish or fish oil may be associated with a reduced risk of eczema in offspring, although further studies are needed. There is some evidence that partially hydrolysed infant formulas rather than standard formulas may be associated with a reduced risk of eczema in infants, but there are shortcomings in the existing evidence. An inverse relationship has been found between gliomas/acute lymphoblastic leukaemia and allergic disease/eczema, but there appears to be no association between multiple sclerosis and eczema. Attention deficit hyperactivity disorder does appear to be associated with eczema, but there is no evidence of a causal link. The risk of eczema seems to be increased in urban compared with rural areas. Some new evidence has suggested superiority of 1% pimecrolimus over potent and mild corticosteroids at 6 months but not 12 months, and there is some evidence for superiority of 0.03% and 0.1% tacrolimus over 1% pimecrolimus. An updated Cochrane Review still found no evidence of a benefit from any form of antistaphylococcal treatment in managing clinically infected or uninfected eczema. The evidence base is poor for bath emollients, occlusive treatments (e.g. wet and dry wraps) and woven silk clothing in treating eczema. In general, the methods used in most systematic reviews of eczema need to be reported more clearly, especially with regard to a more vigorous quality assessment of included studies. Included studies are frequently heterogeneous, proxy reporting is common, and appropriate disease definitions are often lacking. Better adherence to existing guidance on trial reporting and prospective registration of clinical trials may help improve the quality of studies.
This review summarizes the findings of 18 systematic reviews on the topic of atopic eczema, which were indexed in bibliographic databases between January 2009 and 24 August 2010 and were included in the 2010 Annual Evidence Based Update on Atopic Eczema from NHS Evidence – skin disorders. We recommend this article be read in conjugation with the original reports cited, and the full review, where the search methods and omitted reviews are detailed (http://www.library.nhs.uk/skin/ViewResource.aspx?resID=386959&tabID=289&catID=8310). This review only includes systematic reviews, as they are generally considered more reliable evidence compared with randomized controlled trials (RCTs), which are often contradicted by subsequent studies.1 Reviews summarizing previous Annual Evidence Updates on atopic eczema have been published previously in this journal.2–5
Diet and eczema risk
There is considerable interest in putative links between diet and atopic eczema (AE). For instance, the demand for organic foods in the UK remains high, in part owing to a perception that they are associated with health benefits over conventionally produced foods. Dangour et al.6 aimed to assess the evidence for any health effects of organic foods, but failed to find any health benefits. Of the 12 studies included, one Dutch birth cohort study reported a reduction in eczema risk in children given organic dairy products only, although the study failed to adjust adequately for confounding variables.7 It is not possible to recommend organic foods for the purposes of reducing eczema risk based on this review.
Omega-3, a polyunsaturated fatty acid, which is found in fish and fish oils, has been suggested to decrease the risk of AE, and was the subject of a systematic review by Kremmyda et al.8 Data from some observational studies and RCTs show some benefit of fish oil supplementation during pregnancy in terms of eczema risk in offspring; however, the included studies were very heterogeneous and the methods used in the review itself were poorly explained.
Food as a potential allergen
The topic of food allergy remains important to many parents of children with AE, and was the subject of a systematic review by Chafen et al.9 The review was very wide in its scope, which, coupled with the heterogeneity in the 72 included studies, precludes a meta-analysis. The review emphasized that better standardization of the definition and diagnosis of food allergy is urgently needed. The review informed guidelines on the management of food allergies published by The National Institute of Allergy and Infectious Diseases in the USA,10 and we anticipate the imminent publication of UK guidelines by the National Institute of Health and Clinical Excellence (NICE).
It has been hypothesized that hydrolysing cow milk protein will reduce its allergenicity, and thereby the risk of eczema in infants fed formula milk. A systematic review by Alexander and Cabana explored the relationship between partially hydrolysed formulas (PHF) and eczema risk; it was sponsored by Nestlé, which is a manufacturer of PHF.11 A meta-analysis suggested a reduced eczema risk when infants are fed PHF [relative risk (RR) = 0.55; 95% CI 0.4–0.76], an effect that is narrowly sustained until the age of 3 years. The review had methodological shortcomings, and contradicted a previously published Cochrane Review, which found some benefit with the use of extensively hydrolysed formulas, but no effect with PHF in eczema reduction in children.12 Nestlé has funded two similar reviews covering the same subject area, both yielding results comparable with the Alexander and Cabana review.13,14
Eczema and disease associations
Several studies have explored the possible links between a range of conditions and atopic diseases and eczema. A meta-analysis by Chen et al.15 demonstrated a reduced risk of developing gliomas in patients with allergic diseases in general [odds ratio (OR) = 0.60; 95% CI 0.52–0.61] and eczema (OR = 0.69; 95% CI 0.62–0.78). The inverse relationship appeared to be consistent across the included studies despite the degree of heterogeneity between them.
A systematic review by Linabery et al.16 found another inverse relationship between the risk of developing acute lymphoblastic leukaemia (ALL) and atopy/allergy (OR = 0.69; 95% CI 0.54–0.89) and eczema.
It has been reported that the prevalence of both attention deficit hyperactivity disorder (ADHD) and eczema is rising. A systematic review by Schmitt et al.17 included 20 studies, 6 of which showed an association between eczema and ADHD. However, prospective cohort studies are better able to separate cause form effect in this context, and the only cohort study included in the review demonstrated a weak association after adjusting for confounding variables (OR = 1.19; 95% CI 0.88–1.61). Larger prospective studies will be needed to explore any association further.
A link has also been suggested between eczema and multiple sclerosis (MS). A meta-analysis of 10 studies by Monteiro et al.18 failed to detect any such association; however, a lack of consistency in terms of disease definitions in included studies could lead to existing associations remaining undetected.
Increasing urbanization, the rising incidence of eczema and observed social-class gradients are consistent with eczema having possible environmental triggers. Schram et al.19 explored whether there is an urban–rural gradient in eczema prevalence. This review included 26 studies, 11 of which showed a significantly increased risk of eczema in urban areas (with a stronger association in ‘developing’ countries), although 6 studies showed the opposite trend. Significant heterogeneity precluded a meta-analysis, and methodological shortcomings in included studies limit the conclusions that could be drawn.
Topical and antibacterial therapies
Bath emollients are often used as part of eczema management. Tarr and Iheanacho20 explored evidence from RCTs that evaluated their use. These authors found no studies on bath emollients, nor any studies comparing them with directly applied emollients, thus highlighting an area where new research is needed.
Calcineurin inhibitors in the treatment of eczema are better studied. Fleischer and Boguniewicz21 aimed to evaluate the use of tacrolimus on pruritus in AE, in a review sponsored by Astellas, the manufacturer of tacrolimus. Of the 23 included studies, 5 showed a reduction in pruritus when using tacrolimus as opposed to vehicle, although a comparison with topical corticosteroids would have been more helpful in guiding clinical practice. The absence of quality assessment and statistical analyses in the review makes it difficult to confidently recommend topical tacrolimus to manage pruritus based on the presented data.
A more general systematic review by Chen et al.22 evaluated the efficacy and safety of topical calcineurin inhibitors. Meta-analysis of two trials suggested possible superiority of pimecrolimus over corticosteroids at 6 months (OR = 1.59; 95% CI 1.20–2.11), but not at 12 months. Two of three trials found evidence of superiority of 0.03% tacrolimus over 1% pimecrolimus. There was a very wide range of adverse events, making it difficult to recommend one treatment over another on this basis. In particular, longer-term data are needed in light of concerns over possible carcinogenicity, although no evidence of a causal link exists at present.
A previous Cochrane Review found little evidence of benefit from using antistaphylococcal treatment in eczema. An updated review this year by Bath-Hextall et al.23 included five new RCTs, including a study of bleach added to baths, but still found no convincing evidence of a therapeutic benefit from antistaphylococcal treatment in clinically infected or uninfected eczema.
Occlusion of the skin of patients with eczema (e.g. dry wraps and wet wraps) is widely used. A review by Bragham et al.24 explored the evidence base for their use. The 18 included studies were generally of poor quality, and provided little useful evidence for or against occlusion.
Silk clothing as a means to manage eczema has received some attention recently, in particular DermaSilk clothing (Espère Healthcare Ltd., Bedford, UK), which is manufactured form woven silk that is impregnated with the antibacterial agent AEGIS AEM 5772/5. A systematic review by Vlachou et al.25 found little good evidence to support its use in the clinical setting, which in part was the result of severe methodological shortcomings in the few small studies that have been carried out to date.
The implications for practice of the systematic reviews found are summarized in the box below. Several systematic reviews failed to adequately declare search strategies, and quality assessment was frequently inadequate or completely absent. Reviews of interventions that are sponsored by manufacturers of the product concerned tended to be ‘positive’, raising concerns over selection bias and hence their validity.
Considerable heterogeneity, proxy reporting and a failure to adequately define eczema in studies are other reasons that limit the usefulness of many systematic reviews. Such methodological inadequacies may lead to a failure to detect true treatment effects and disease associations. Prospective registration in trials databases and adherence to guidelines on trial reporting (e.g. by the CONSORT group) provide two strong means to ensure better quality of future knowledge translation.26
To demonstrate up-to-date knowledge of recent evidence for the causes, disease associations, prevention and treatment of atopic eczema.
Which of the following conditions occurs less frequently in people with atopic eczema?
b) Multiple myeloma
c) Attention deficit hyperactivity disorder
d) Acute myeloid leukaemia
e) Multiple sclerosis
Fish oil supplementation/increased fish intake may reduce the risk of atopic eczema in children if given to which one of the following groups?
b) Pregnant mothers
c) Breastfeeding mothers
d) Fathers of expectant mothers
Partially hydrolysed infant formulas are thought to reduce the risk of atopic eczema in infants for which reason?
a) Through complete avoidance of cow milk protein
b) Through more rapid digestion of the formula
c) Through the intake of soy-derived proteins
d) Through reducing the allergenicity of the formula
e) Through a reduction in gastrointestinal transit time
In terms of treatment for eczema, which of the following have good evidence to support clinically useful benefit?
a) Bath oils
b) Silk clothing
c) Topical calcineurin inhibitors
d) Antistaphylococcal treatment in clinically infected or uninfected eczema
e) Topical Chinese herbs
Current evidence suggests that organic foods may reduce atopic eczema risk in which setting?
a) Consumption of organic foods only during pregnancy
b) Organic fruits/vegetables given to children
c) Consumption of organic dairy foods in pregnancy
d) Organic dairy foods given to children
e) Consumption of organic food only if there is a family history of atopy
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