What is the evidence base for atopic eczema treatments? A summary of published randomized controlled trials

Atopic eczema (AE) is a common chronic inflammatory skin condition. While many AE treatment options are available, the evidence to support their efficacy varies in depth and quality. In 2000, a National Institute for Health Research (NIHR) Health Technology Assessment systematic review identified and evaluated existing randomized controlled trials (RCTs) of AE treatments. To ensure continuing utility, the NIHR commissioned an update to the review. Here, we present an overview of the updated report and its key findings. Systematic reviews and RCTs of AE treatments that included participants with AE (criteria based or diagnosed) were identified using Medline, Embase, CENTRAL, Latin American and Caribbean Health Sciences, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature and Cochrane Skin Group Specialised Register [searched to 31 August 2013 (RCTs) and 31 December 2015 (systematic reviews)]. Outcome measures included symptoms, AE severity, quality of life and adverse effects. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Of the 287 new RCTs identified, only 22 (8%) were judged to have a low risk of bias. When combined with RCTs from the previous review (n = 254), we found ‘reasonable evidence of benefit’ for corticosteroids, calcineurin inhibitors, Atopiclair®, ciclosporin, azathioprine, ultraviolet radiation and education programmes. Interventions with reasonable evidence of ‘no benefit’ included some dietary interventions, ion exchange water softeners, multiple daily applications of topical corticosteroids and antibiotic‐containing corticosteroids for noninfected AE. Many common treatments lack evidence of efficacy and warrant further evaluation. The evidence base for AE is still hampered by poor trial design and reporting. The trials included in this review were used to establish the Global Resource of EczemA Trials (GREAT) database.

Atopic eczema (AE) (also known as atopic dermatitis), is a chronic inflammatory skin condition characterized by an itchy red rash that affects all age groups. 1 AE has one of the highest burdens compared with other skin diseases. 2 The evidence base for AE treatments is extensive, but has limitations in terms of quality and relevance. 3 This is exemplified by the 'Systematic Review of Treatments for Atopic Eczema', published by the National Institute for Health Research (NIHR), which identified 254 randomized controlled trials (RCTs) of AE treatment covering 47 interventions. 4 The encompassing nature of the review, and critical appraisal of the evidence therein, has helped to inform clinical guidelines on an international level for over a decade and the report has been heavily cited, with more than 650 citations listed in Google Scholar at the time of writing. [5][6][7][8] To ensure its continuing utility, the NIHR commissioned an update of the systematic scoping review as part of a programme of work on the prevention and treatment of skin disease, 9 with the aim of summarizing the evidence base for AE treatments for guideline writers, healthcare professionals and patients. This review will also help in identifying research gaps to be addressed in the future, and to identify topics suitable for specific targeted systematic reviews.
The current paper provides a summary of the updated scoping review (which is freely available through the NIHR journal series), 9 with a specific focus on the overall findings and conclusions.

Methods used for the scoping review
The following section briefly describes the methodology employed to create the scoping review, which can be viewed in its entirety in the methods section of the full report. 9 Design This was a systematic scoping review of all systematic reviews and RCTs for AE treatments. A scoping review attempts to map systematically existing evidence on a given topic and identify potential gaps in the literature to inform future research priorities. It differs from a clinically focused systematic review in that it often covers a much broader topic area, summarizes the evidence in a qualitative format and offers limited critical appraisal. 10

Type of studies included
As systematic reviews and RCTs represent the best source of unbiased evidence on the effectiveness of treatments, we included only these types of studies. Studies were required to contain at least one clinical outcome. Prevention studies, provocation studies, changes in blood biochemistry and evaluations of cellular mechanisms were excluded.

Participants
Studies were included if participants (of any age) had AE, as diagnosed by a physician, or that met with diagnostic criteria (e.g. Hanifin and Rajka, 11 U.K. working party 12 or similar).

Main outcome measures
Outcome measures chosen for the review were deliberately broad, in order to reflect those commonly used in AE trials. 13,14 Changes in patient-rated symptoms such as itching (pruritus) or sleep loss were extracted where possible. Global severity, as rated by patients or their physician, was also sought. Other outcomes included changes in AE severity rating scales, quality of life and adverse events (encompassing adverse events and adverse reactions depending on how these were reported in the original RCTs).

Search strategy
We searched the following electronic databases (search dates end of 1999 to 31 August 2013): Medline, Embase, CEN-TRAL, The Cochrane Skin Group Specialised Trials Register, Latin American and Caribbean Health Sciences database (LILACS); Allied and Complementary Medicine Database (AMED); Cumulative Index to Nursing and Allied Health Literature (CINAHL) ( Fig. S1; see Supporting Information). We also searched http://www.controlled-trials.com for completed and ongoing RCTs using the terms 'atopic dermatitis', 'atopic eczema' and 'eczema' as well as using our extensive contacts in the field of AE research to identify other ongoing studies.
Systematic reviews on AE treatments were searched up to December 2015 using PubMed, Embase, the Cochrane Library and NHS Evidence. Where appropriate, the results of these specific systematic reviews are presented alongside the RCT evidence.
We used the following disease terms for AE: 'atopic dermatitis', 'atopic eczema', 'eczema', 'neurodermatitis', 'infantile eczema', 'childhood eczema' or 'Besniers' prurigo'. No language restrictions were applied; data from non-English papers were extracted by international colleagues. References were screened by one author (either S.S. or H.N.), and there was discussion with a second author as required (H.C.W., K.S.T. or S.B.). Those studies using terms that were definitely not AE, such as 'allergic contact eczema', were excluded. Terms that were considered possibly AE, such as 'childhood eczema', were scrutinized and included only if the description of the participants clearly indicated AE.

Data assessment and study quality
Data were independently extracted by two authors (H.N. and S.B. or S.S.) with discrepancies resolved by consensus or by an arbitrator (H.C.W., K.S.T. or F.M.D.). Although primarily a scoping review, trial quality (specifically randomization, allocation concealment and blinding) was evaluated. This was done using the Cochrane Collaboration's risk of bias assessment tool. 15 The overall risk of bias for the included studies was summarized according to defined criteria (Supplementary Table S1; see Supporting Information). Authors were not blinded to the identity of the RCT authors, and a more detailed quality assessment (such as GRADE) 16 was unfeasible given the number of included studies.

Presentation of the results
Results are presented according to the following broad categories of treatments: (i) topical corticosteroids and topical immunomodulators; (ii) emollients and other topical treatments (including bath additives and oils); (iii) antimicrobials including antibiotics, antiseptics and antifungals, (iv) antihistamines and mast-cell stabilizers; (v) dietary interventions (including probiotics, essential fatty acids, vitamins, cows' milk substitutes); (vi) nonpharmacological interventions (including education, psychological therapies, different ways of providing AE care, allergen avoidance followed by allergen avoidance or reintroduction and medical devices); (vii) phototherapy; (viii) systemic immunomodulatory agents; (ix) complementary therapies (homeopathy, aromatherapy, hypnotherapy, Chinese herbal medicine, St John's Wort, acupuncture, balneotherapy, relaxation) and (x) other.
For clarity of interpretation, results are also summarized according to the following categories of evidence: (i) treatments for which there is reasonable evidence of benefit (ii) treatments for which there is reasonable evidence of no clinically useful benefit (iii) treatments for which there is insufficient evidence to inform clinical decision making (iv) treatments with an absence of RCT evidence Classification of treatment options into these four categories was a qualitative judgement on the part of the authors based on availability and quality of the evidence, and the likelihood of clinically important effects. It is not intended to signify that all uncertainty has been resolved in those areas classed as having reasonable evidence of benefit or reasonable evidence of no benefitsimply that there is a reasonable body of evidence that may usefully inform clinical decision making. In this paper, we have not tried to summarize the possible harms of all included studies, but harms and drawbacks of treatments are included for all treatment categories in the main report.
Pooling of the trial results using meta-analysis was not possible owing to the very wide nature of the interventions included, and the very heterogeneous nature of the study participants and outcomes. However, interventions with evidence of benefit or evidence of no benefit have been mapped to the latest relevant systematic reviews on these topics where they exist.

Results of the review Summary of trials
In addition to the 254 RCTs identified in the original 2000 scoping review, this updated review includes an additional 287 new RCTs, making 541 RCTs in total covering 92 different interventions for treating AE. The number of RCTs published according to broad treatment categories is shown ( Fig. 1), with further details provided in Figure S2 (see Supporting Information).  The size of the newly identified RCTs varied widely from seven randomized participants to 972 participants. Most of the trials were conducted in secondary care, and tended to include participants with either moderate-to-severe disease or mild-to-moderate disease. Very few RCTs included all severities of AE.
Reporting was generally poor, with 'unclear' categories dominating the assessments; randomization method (2% high, 36% low and 62% unclear risk of bias), allocation concealment (3% high, 15% low and 82% unclear risk of bias) and blinding or masking of the intervention (15% high, 28% low, 57% unclear risk of bias). Only 22 of 287 studies (8%) were considered to be at low risk of bias for all three quality criteria (randomization, allocation concealment and blinding). Overall agreement between the team members on the availability and quality of the evidence, and the likelihood of clinically important effects, was good.

Treatments with reasonable evidence of benefit
Fourteen interventions or treatment approaches were felt to have reasonable evidence of benefit (Table 1). These include the use of topical corticosteroids and topical calcineurin inhibitors, both for the treatment of active AE and as intermittent proactive (maintenance) therapy for the prevention of AE flares. Other interventions including Atopiclair â emollient, ultraviolet light therapy, azathioprine and ciclosporin. All had reasonable evidence of benefit compared with placebo/vehicle. Similarly, RCT and systematic review evidence suggested that education may be beneficial, although the exact components of a successful education programme in different clinical settings are still unclear.
Of the 14 interventions with reasonable evidence of benefit, 10 of 14 (71%) have been the subject of more detailed, treatment-specific systematic reviews (Table 1).

Treatments with evidence of no clinically useful benefit
Nine interventions were deemed to have a reasonable level of evidence of no benefit in treating AE (Table 2). These included the use of topical corticosteroids containing an antibiotic for the treatment of AE that is not infected, Mycobacterium vaccae vaccine, probiotics, ion exchange water softeners, evening primrose oil and borage oil.
Treatments that require more research There are many treatments for AE that have insufficient or contradictory RCT evidence, for which further research is required ( Table 3). Some of the treatments have been trialled many times; however, the quality of reporting means that evidence for these treatments is not yet strong enough.

Treatments with an absence of randomized clinical trial evidence
The scoping review has helped to identify areas where there is currently no RCT evidence for commonly used practices for the treatment of AE including dilution of topical corticosteroids, order of application of topical corticosteroids and emollients, impregnated bandages (zinc or ichthammol paste bandages), modified bathing habits (nonantiseptic bath additives, soap avoidance, frequency of bathing), and the role of routine allergy testing followed by allergen avoidance or reintroduction.

Discussion
The systematic scoping review findings indicated that there was only a small number of treatments with evidence of benefit (Table 1) and some treatments with evidence of no benefit (Table 2). However, for the majority of treatments, further better-designed research is needed (Table 3). It is disappointing that there was a lack of a strong evidence base for some of the most widely used AE treatments, such as emollients and bandages. However, stopping or restricting the use of these treatments on the basis of a lack of RCT evidence would not benefit patients. Although information on treatment drawbacks and harms are included for each intervention in the main review, we have not tried to summarize them in this report because of their diverse and treatment-specific nature. Generally, harms were reported less well than treatment benefits, resulting in an asymmetry of information to inform patient choices.
In addition to the established approach for treating AE flares with topical corticosteroids, perhaps the single largest advance in AE treatment since the 2000 review has been the strong evidence supporting the value of a proactive approach for maintaining AE remission through the use of twice-weekly topical corticosteroids or calcineurin inhibitors. 17 Educational approaches have also emerged as a potentially promising Evidence of no benefit: at least one good quality randomized controlled trial (RCT) or several less well reported RCTs that consistently failed to show a convincing benefit on overall disease activity. We defined a 'good quality' trial as well designed and well reported, and large enough to exclude a clinically useful benefit or several trials with no evidence of benefit to give confidence in there being no clinically relevant benefit, despite less clear reporting intervention, although further work is needed to establish the most important components of the intervention, and the most cost-effective ways of delivering education in different healthcare settings. The finding that Atopiclair â emollient has emerged as a potentially useful intervention for AE in four of five industrysponsored trials is difficult to interpret at this time. Independent high-quality trials that compare Atopiclair â with other commonly used (and cheaper) emollients are now needed.
The understanding that some interventions now have sufficient evidence to suggest little or no benefit for patients with AE is equally important. These interventions provide options for disinvestment, ensuring that available funds are channelled to the most effective treatments. Possible areas to consider for disinvestment include the following: the application of topical corticosteroids twice daily, as once-daily application has been shown to be equally effective; topical corticosteroids containing antibiotics when used for the management of noninfected AE; the use of ion exchange water softeners; and dietary supplements (probiotics, borage oil, evening primrose oil).
There is a lack of AE treatment trials conducted in a primary care setting, where most patients are seen. The research questions being investigated often fail to reflect the most pressing questions for clinicians and patients. A recent James Lind Alliance Priority Setting Partnership 3 identified the most important treatment uncertainties as judged by patients and clinicians. When set in the context of the updated evidence base from the review, the following areas identified from the Priority Setting Partnership seem to be most pressing: Priority areas with no current RCT evidence • What role might allergy tests play in treating AE?
• What is the best way for people with AE to wash? • Which should be applied first when treating AEemollients or topical corticosteroids?

Priority areas with limited RCT evidence
• What is the best and safest way of using topical corticosteroids for AE?
• What is the long-term safety of applying topical steroids to the skin for AE? • Which emollient is the most effective and safe in treating AE?
• What is the best psychological treatment for itching/ scratching in AE?
• What are the best and safest 'natural' products to apply to the skin?
• How much does avoidance of irritants and allergens help people with AE?
• What is the role of diet in treating AE (exclusion diets and nutritional supplements)?
• Which is more effective in the management of AE: education programmes, general practitioner care, nurse-led care, dermatology-led care of multidisciplinary teams?
• Which is safer and more effective in treating AE: topical corticosteroids or calcineurin inhibitors (especially for proactive flare prevention)?
• How effective are interventions to reduce skin infections in the management of AE?
• What is the best and safest way of using drugs that suppress the immune system (particularly in children)?
Some important topics have already been picked up by NIHR funding bodies, and large pragmatic trials are currently underway in the U.K. evaluating the role of topical and oral antibiotics for the treatment of infected AE (CREAM) (UKCRN ID 11233), silk clothing for the management of moderate-tosevere AE (CLOTHES) (UKCRN ID 15132), the role of bath emollients in the management of AE (BATHE: UKCRN ID 17348) and a feasibility trial of the emollient clinical effectiveness and cost-effectiveness (COMET: UKCRN ID 16571).
One of the most pressing concerns identified by this review is the continued preponderance of small, poorly reported and poorly conducted trials. Greater efforts to work collaboratively to conduct large, well-designed studies that address important questions, can only be of benefit to patients and healthcare providers.
Similarly, the ability to combine study results in meta-analysis continues to be hampered by the wide variation in outcome measures used. The move towards using the same core outcome sets, as encouraged by the Harmonising Outcome Measures for Eczema (HOME) initiative 18-20 (www.homeforec zema.org), is likely to be beneficial for future clinical interpretation and evidence syntheses.
The updated review has used a clear methodology for identifying RCTs for inclusion, which has minimized potential selection bias. However, despite searching the main bibliographical databases (Medline and Embase) and several smaller, specialist databases (CINAHL, AMED and LILACS), it is possible that we might have missed some RCTs. Many of the treatments that are lacking in RCT evidence have nevertheless been studied using uncontrolled designs, which may provide additional useful information. Similarly, large cohort studies are required to detect rare treatment adverse effects.
It was not practical to mask the identity of the trial authors from the review team and this may have introduced bias when summarizing qualitative aspects of the results. Given the very wide scope of the review and heterogeneous nature of participants, interventions and outcomes, it was not practical to undertake detailed meta-analysis for single interventions. These will need to be conducted in the future (where appropriate) within much narrower intervention-specific systematic reviews.
Our classification of treatment options into categories such as 'evidence of benefit to support' is not tantamount to a positive recommendation for widespread use or otherwise, as that is the remit of guideline developers and depends on factors such as magnitude of benefit, adverse effects, how the treatment compares with existing active treatments, availability, cost-effectiveness and population most likely to benefit.
As with all systematic reviews, the evidence presented will become out of date quite rapidly for some topics, and readers of the review are also directed to our free-to-access database of AE RCTs Global Resource of EczemA Trials (GREAT database, accessible at http://www.greatdatabase.org.uk), which contains details of all the studies in the scoping review and can be used by readers who wish to investigate particular included or excluded studies further.
The number of RCTs for AE has increased substantially since the year 2000, 4 yet most are still small, poorly reported and do not address questions of clinical importance to patients and healthcare professionals.
We hope that our work provides an easily accessible guide for patients and clinicians wishing to research treatment effects, and that it will be used by guideline developers to prevent duplication of effort in collating and evaluating the available evidence base for AE treatments. AE researchers will be able to identify potential research gaps and systematic reviews that require further work.