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Hoare C, Li Wan Po A, Williams H. Systematic review of treatments for atopic eczema. Southampton (UK): NIHR Journals Library; 2000 Dec. (Health Technology Assessment, No. 04.37.)
Atopic eczema is a chronic inflammatory skin condition characterised by an itchy red rash that favours the skin creases such as folds of elbows or behind the knees. The eczema lesions themselves vary in appearance from collections of fluid in the skin (vesicles) to gross thickening of the skin (lichenification) on a background of poorly demarcated redness. Other features such as crusting, scaling, cracking and swelling of the skin can occur.1 Atopic eczema is associated with other atopic diseases such as hay fever and asthma. People with atopic eczema also have a dry skin tendency, which makes them vulnerable to the drying effects of soaps. Atopic eczema typically starts in early life, with about 80% of cases starting before the age of 5 years.2
Although the word ‘atopic’ is used when describing atopic eczema, it should be noted that around 20% of people with otherwise typical atopic eczema are not atopic as defined by the presence of positive skin prick test reactions to common environmental allergens, or through blood tests, which detect specific circulating immunoglobulin E (IgE) antibodies.3 The word ‘atopic’ in the term atopic eczema is simply an indicator of the frequent association with atopy and the need to separate this clinical phenotype from the ten or so other forms of eczema such as irritant, allergic contact, discoid, venous, seborrhoeic and photosensitive eczema, which have other causes and distinct patterns. The terms atopic eczema and atopic dermatitis are synonymous. The term atopic eczema or just eczema is frequently used in the UK, whereas atopic dermatitis is used more in North America. Much scientific energy has been wasted in debating which term should be used.
Very often, no definition of atopic eczema is given in clinical studies such as clinical trials. This leaves the reader guessing as to what sort of people were studied. Atopic eczema is a difficult disease to define as the clinical features are highly variable. This variability can be in the skin rash morphology (e.g. it can be dry and thickened or weeping and eroded), in place (e.g. it commonly affects the cheeks in infants and skin creases in older children) and time (it can be bright red one day and apparently gone in a couple of days). There is no specific diagnostic test that encompasses all people with typical eczema and which can serve as a reference standard. Diagnosis is therefore essentially a clinical one.
Up until the late 1970s, at least 12 synonyms for atopic eczema were in common usage in the dermatological literature, and it is not certain if physicians were all referring to the same disease when using these terms. A major milestone in describing the main clinical features of atopic eczema was the Hanifin and Rajka diagnostic criteria of 1980.4 These are frequently cited in clinical trial articles, and they at least provide some degree of confidence that researchers are referring to a similar disease when using these features. It should be borne in mind however that these criteria were developed on the basis of consensus, and their validity and repeatability is unknown in relation to physician's diagnosis.3 Some of the 30 or so minor features have since been shown not to be associated with atopic eczema, and many of the terms, which are poorly defined, probably mean something only to dermatologists. Scientifically developed refinements of the Hanifin and Rajka diagnostic criteria, mainly for epidemiological studies, have been developed by a UK working party, and these criteria have been widely used throughout the world.5 According the these criteria,6 in order to qualify as a case of atopic eczema, the person must have:
It is unclear whether atopic eczema is an ‘entity’ in itself or whether it is part of a continuum when considered at a population level. Some studies have suggested that atopic dermatitis score is distributed as part of a continuum.3 Although it may be appropriate to ask the question: “How much atopic eczema does he/she have?” as opposed to “Does he/she have atopic eczema – yes or no?”, most population and clinical studies require a categorical cut-off point and tend to include well-defined and typical cases.
It is quite possible that there are distinct subsets of atopic eczema, for example those cases associated with atopy and those who have severe disease with recurrent infections. Until the exact genetic and causative agents are known, it is wiser to consider the clinical disease as one condition. Perhaps sensitivity analyses can be done for those who are thought to represent distinct subsets (e.g. those who are definitely atopic with raised circulating IgE to allergens, or those with severe disease and associated asthma).3
Atopic eczema is a very common problem. Prevalence studies in the last decade in Northern Europe suggest an overall prevalence of 15–20% in children aged 7–18 years.7 Standardised questionnaire data from 486,623 children aged 13–14 years in the International Study of Asthma and Allergies in Childhood (ISAAC) suggest that atopic eczema is not just a problem confined to Western Europe, with high prevalence found in many developing cities undergoing rapid demographic change.8 There is reasonable evidence to suggest that the prevalence of atopic eczema has increased two- to three-fold over the past 30 years, the reasons of which are unclear.9 No reliable incidence estimates are available for atopic eczema.
Atopic eczema is commoner in childhood, particularly in the first 5 years of life. One study of 2365 patients who were examined by a dermatologist for atopic eczema in the town of Livingston, Scotland, suggested that atopic eczema is relatively rare over the age of 40, with a 1-year period prevalence of 0.2%.10 Nevertheless, adults over 16 years made up 38% of all atopic eczema cases in that community. Adults also tend to represent a more persistent and severe subset of cases.
Most cases of childhood eczema in any given community are mild. One recent study by Emerson and colleagues found that 84% of 1760 children aged 1–5 years from four urban and semi-urban general practices in Nottingham were mild, as defined globally by the examining physician, with 14% of cases in the moderate category and 2% in the severe category.11 Disease severity was not the only determinant of referral for secondary care, however. This severity distribution was very similar to another recent population survey in Norway.12
Direct morbidity has been estimated in several studies using generic dermatology quality-of-life scales. It has been found that atopic eczema usually accounts for the highest scores when compared with other dermatological disease. Specific aspects of a child's life that are affected by atopic eczema are:
Despite the public's tendency to trivialise skin disease, the suffering associated with the intractable itching of atopic eczema can be greater than other illnesses such as asthma and heart disease.
Family disturbance is also considerable with sleep loss and the need to take time off work for visits to healthcare professionals.7
In financial terms, the cost of atopic eczema is potentially very large. One recent study of an entire community in Scotland estimated the mean personal cost to the patient at £25.90 over a 2-month period with the mean cost to the health service of £16.20.13 If these results were extrapolated to the UK population, the annual personal costs to patients with atopic eczema based on lower prevalence estimates than recent studies suggest would be £297 million. The cost to the health service would be £125 million and the annual cost to society through lost working days would be £43 million making the total expenditure on atopic eczema £465 million per year (1995 prices). Another recent study from Australia found that the annual personal financial cost of managing mild, moderate and severe eczema was Aus$330,818 and $1255, respectively, which was greater than the costs associated with asthma in that study.14
There is strong evidence to suggest that genetic factors are important in the predisposition to atopic eczema. In addition to family studies, twin studies have shown a much higher concordance for monozygotic (85%) when compared with dizygotic twins (21%).15 Preliminary work has suggested that a marker for IgE hyper-responsiveness might be located on chromosome 11q, but this has not been consistent. It is possible that the tendency to atopic eczema might be inherited independently from atopy.
While genetic factors are probably a very important factor for disease predisposition, there are numerous general and specific clues that point strongly to the crucial role of the environment on disease expression. 16 It is difficult to explain the large increase in atopic eczema prevalence over the past 30 years, for instance, in genetic terms.9 It has been shown that atopic eczema is commoner in wealthier families.17 It is unclear whether this positive social class gradient is a reflection of indoor allergen exposures or whether it reflects a whole constellation of other factors associated with ‘development’. Other studies have shown an inverse association between eczema prevalence and family size.18 This observation led to the ‘hygiene hypothesis’, that is that children in larger families were protected from expressing atopy because of frequent exposure to infections.19 Some evidence for this protective effect of infections on atopic eczema has been shown in relation to measles infection in Guinea Bissau.20
Migrant studies also point strongly to the role of environmental factors in atopic eczema. It has been shown that 14.9% of black Caribbean children living in London develop atopic eczema (according to the UK diagnostic criteria) compared with only 5.6% for similar children living in Kingston, Jamaica.21 Other migrant studies reviewed elsewhere have consistently recorded large differences in ethnic groups migrating from warmer climates to more prosperous cooler countries.
Further work has suggested that the tendency to atopy may be programmed at birth and could be related to factors such as maternal age.22 The observation that many cases of atopic eczema improve spontaneously around puberty is also difficult to explain in genetic terms alone.2 Specific risk factors for eczema expression in the environment are still not fully elucidated. Allergic factors such as exposure to house dust mite may be important but non-allergic factors such as exposure to irritants, bacteria and hard water may also be important.23
A number of mechanisms and cells are thought to be important in atopic eczema and these are reviewed in detail elsewhere.1,24 Microscopically, the characteristic appearance of eczema is that of excess fluid between the cells in the epidermis (spongiosis). When severe, this fluid eventually disrupts the adjacent cells in the epidermis to form small collections of fluid, which are visible to the naked eye as vesicles. In the chronic phase, atopic eczema is characterised by gross thickening of the epidermis (acanthosis) and an infiltrate of lymphocytes in the dermis. The theory that unifies the various abnormalities of atopic eczema suggest that blood stem cells carrying abnormal genetic expression of atopy cause clinical disease as they infiltrate and remain in the mucosal surfaces and skin. There appears to be a failure to switch off the natural predominance of Th2 helper lymphocytes, which normally occurs in infancy, and this leads to an abnormal response of chemical messengers called cytokines to a variety of stimuli. The underlying mechanism of disease may be either abnormalities of cyclic nucleotide regulation of marrow-derived cells or allergenic over-stimulation that causes secondary abnormalities. Some studies have suggested a defect in lipid composition and barrier function of people with atopic eczema – a defect that is thought to underlie the dry skin tendency and possibly enhanced penetration of environmental allergens and irritants, leading to chronic inflammation.
Although the tendency towards a dry and irritable skin is probably lifelong, the majority of children with atopic eczema appear to ‘grow out’ of their disease, at least to the point where the condition no longer becomes a problem in need of medical care. A detailed review of studies that have determined the prognosis of atopic eczema has been reported elsewhere.2 This review suggested that most large studies of well-defined and representative cases suggest that about 60% of childhood cases are clear or free of symptoms from disease in early adolescence. Many such apparently clear cases are likely to recur in adulthood, often as hand eczema. The strongest and most consistent factors that appear to predict more persistent atopic eczema are early onset, severe widespread disease in infancy, concomitant asthma or hay fever and a family history of atopic eczema.
The management of atopic eczema in the UK was summarised in a paper jointly produced by a British Association of Dermatology and Royal College of Physicians Working Party in 1995.25 The article described the management of atopic eczema in three stages. The first line of treatment involved providing an adequate explanation of the nature of disease as well as advice on avoiding irritants. The role of emollients in adequate quantities was emphasised, as well as prompt treatment of secondary infections. Topical steroids were highlighted as the mainstay of treatment, though care regarding the duration of treatment, site and age of the person treated was emphasised. Antihistamines were only recommended for their sedative action. Cognitive behavioural techniques were also mentioned as being important to some families. Allergen avoidance, for example the reduction of house dust mite or dietary intervention, was described as a second-line treatment, as was treatment with ultraviolet light under specialist care. Third-line treatment (always under the care of a specialist) included such treatments as short bursts of systemic corticosteroids, cyclosporin A, evening primrose oil and Chinese herbal medicines.
These recommendations were made on the basis of consensus from a wide range of practitioners and patient advocates. Although some recommendations were based on RCTs, many were not. It is unclear, therefore, how many of these recommendations are truly beneficial to patients. New developments since the publication of these recommendations include increased use of a double layer of protective bandages (‘wet-wraps’) with or without topical steroids, ‘newer’ once-daily topical corticosteroids such as mometasone and fluticasone, and possibly some increased use of potent systemic agents such as cyclosporin A. Other new potent topical preparations such as tacrolimus and ascomycin derivatives are probably going to become available in the near future.26
Most children with atopic eczema in the UK are probably managed by the primary care team. This includes advice from pharmacists, health visitors, practice nurses and family practitioners. About 4% of children with atopic eczema are referred to a dermatologist for further advice.11
The quality of service provided by secondary care for eczema sufferers has recently been audited by the British Association of Dermatologists. Although most departments provided a high-quality service, some aspects of care, such as the administration of simple standardised record forms could be improved.27,28
Compliance (or more correctly, concordance) seems to be a major cause of apparent treatment failures and a recent study suggested that this was often due to a poor understanding of the chronic nature of the disease, a fear of topical corticosteroids and the belief that all atopic eczema is caused by a specific allergy. A survey in Nottingham has found that most mothers worry that topical steroids cause adverse effects, though many were not able to distinguish between weak and strong ones.29
The National Eczema Society is the UK's self-help organisation for atopic eczema sufferers and people with other forms of eczema. It has a well-organised information service and national network of activities geared to help eczema sufferers and their families. Sources of alternative care for atopic eczema sufferers abound in the community ranging from the highly professional to elaborate expensive diagnostic and therapeutic measures of dubious value.
Outcome measures used in trials have recently been reviewed by Finlay.30 Most outcome measures have incorporated some measure of itch as assessed by a doctor at periodic reviews or patient self-completed diaries. Other more sophisticated methods of objectively recording itch have been tried. Finlay drew attention to the profusion of composite scales used in evaluating atopic eczema outcomes. These usually incorporate measures of extent of atopic eczema and several physical signs such as redness, scratch marks, thickening of the skin, scaling and dryness. Such signs are typically mixed with symptoms of sleep loss and itching and variable weighting systems are used. It has been shown that measuring surface area involvement in atopic eczema is fraught with difficulties,31 which is not surprising considering that eczema is, by definition, ‘poorly-defined erythema’. Charman and colleagues recently performed a systematic review of named outcome measure scales for atopic eczema and found that of the 13 named scales in current use, only one (Severity Scoring of Atopic Dermatitis, SCORAD) had been fully tested for validity, repeatability and responsiveness.32 Quality-of-life measures specific to dermatology include the Dermatology Quality of Life Index30 and SKINDEX.33 The Children's Dermatology Life Quality index has been used in atopic eczema trials in children.
The authors are aware that most clinical trials of atopic eczema have been short term, that is about 6 weeks. This seems inappropriate in a chronic relapsing condition. Very few studies have considered measuring number and duration of disease-free relapse periods. It is impossible to say whether modern treatments have increased chronicity at the expense of short-term control in the absence of such long-term studies.
The authors suspect that little research has been done into primary and secondary prevention of atopic eczema. Research is also probably very limited in non-pharmacological areas of treatment such as psychological approaches to disease management. Even for traditional pharmaceutical preparations, the choice of treatments for atopic eczema by patients or their practitioners is complicated by a profusion of preparations whose comparative efficacy is unknown.5 Thus, the current British National Formulary lists 19 classes of topical corticosteroids available for treating atopic eczema and a total of 63 preparations that combine corticosteroids with other agents such as antibiotics, antiseptics, antifungals and keratolytic agents.34 How can a family practitioner make a rational choice between so many preparations?35
Systemic treatments for severe atopic eczema have only been partially evaluated. There are plenty of trials, for instance on expensive drugs such as cyclosporin A (which may have serious long-term adverse effects), yet to the best of our knowledge, there is not a single controlled trial on oral azathioprine – a much cheaper and possibly safer and more effective treatment that is currently widely used by British dermatologists.36 In other areas, there is a profusion of small studies, which do not have the power to adequately answer the therapeutic questions posed.
The authors are also aware that many clinical trials have not asked patients enough of what they think about the various treatments under test. There is an opportunity in a systematic review, therefore, to redress the balance of outcome measures used in clinical trials towards the sort of measures that are clinically meaningful to patients and their carers.
Public concern over long-term adverse effects such as skin thinning and growth retardation from use of topical corticosteroid preparations has not been matched by long-term studies on atopic eczema sufferers. Individuals with atopic eczema often resort to self-prescribed diets, which can be nutritionally harmful, or they may turn to ‘alternative’ tests and treatments which may turn out to be beneficial or expensive and harmful.
Thus, there is considerable uncertainty about the effectiveness of the prevention and treatment of atopic eczema. This combination of high disease prevalence, chronic disability, high financial costs, public concerns regarding adverse effects, lack of evaluation of non-pharmacological treatments, concern regarding the clinical relevance of trial outcome measures and the profusion of treatments and care settings of unknown effectiveness is why a scoping systematic review of atopic eczema treatments is needed. It is hoped that the review will form the basis for identifying, prioritising and generating further primary, secondary and methodological research.
The remit of this project is to provide a summary of RCTs of atopic eczema with the main aim of informing the NHS R&D Office and other research commissioners of possible research gaps for further primary, secondary or methodological research. It is also hoped that the review will be of some use to healthcare providers, physicians involved in the care of people with atopic eczema and also to atopic eczema sufferers and their families by placing current treatments in context with their evidence base. The main research questions asked in this review are therefore:
It is unrealistic to attempt to summarise the entire ‘treatments of atopic eczema’ into a single Cochrane-style systematic review, as such a task would take years and cover several volumes. Atopic eczema is a complex disease with at least 40 different treatment approaches and specific questions that can be asked of each treatment group. What is more realistic is to produce a ‘sketch’ or ‘map’ of RCTs of atopic eczema, to quantitatively summarise a few areas of conflicting studies where possible, and to qualitatively review the others in a form that would be helpful to clinicians and patients. Such an approach could also act as ‘seed reviews’ for subsequent, more detailed Cochrane systematic reviews.
The very broad-ranging scoping nature of this review implies that it cannot be hypothesis-driven. Even in just one area of atopic eczema management such as dietary prevention, there are at least six separate systematic reviews that can be asked of the available data:
Trying to answer similar questions for each of the 40 or so interventions used for the treatment of atopic eczema would be impossible in one short report.
This review is therefore unashamedly a data-driven one. It is a review that aims to map out what has been done in terms of RCTs in atopic eczema to date and to reflect and comment on the coverage of already researched areas in relation to questions that are commonly asked by physicians and their patients.
The authors are aware that there is a danger that a data-driven review can serve to amplify and perpetuate current trends in evaluating minor differences between a profusion of similar pharmacological products. The authors have mitigated against this inevitable hazard by drawing attention to gaps that have not been addressed when summarising the reported studies, and also by including a comprehensive section on ‘unanswered questions’ in chapter 14 of this report, based on the views of contemporary researchers, physicians and patients.
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