Complementary and alternative medicine treatments for atopic eczema

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of complementary and alternative medicine treatments for atopic eczema.

Background

Description of the condition

Definition, clinical features, and epidemiology

Atopic eczema (AE) is difficult to define because of its variable morphology and distribution and its intermittent nature (Williams 2005). In infants, the disease typically appears on the face and scalp, while in children, it tends to occur on the hands, feet, wrists, ankles, the popliteal surface (behind the knees), and the antecubital region (in front of the elbows). Adults usually develop AE on the face, neck, back of the hands, and top of the feet (Akdis 2006). Itching is a predominant symptom of AE. It can often lead to a vicious cycle of scratching, which causes skin damage that in turn results in more itching: This is commonly referred to as the itch‐scratch cycle of AE. The diagnosis of AE relies on the assessment of clinical features because there is no definitive test to diagnose the condition. Hanifin and Rajka (Hanifin 1980) originally developed diagnostic criteria for AE, which have subsequently been refined and validated (Williams 1994; Williams 1994a; Williams 1994b; Williams 1996; Williams 2005). A systematic review demonstrated that only the UK Working Party (Williams 1994) diagnostic criteria have been validated more than once and independently (Brenninkmeijer 2008). However, the Hanifin and Rajka diagnostic criteria have long been in use in dermatology, and they have been validated not only by consensus among leading clinical experts on AE but also via some scientific testing, albeit not as extensively as the UK Working Party's diagnostic criteria. Generally, the diagnosis is made in the presence of itchy skin, with three or more of the following: history and visible signs of eczema at areas of skin creases (such as the inner sides of the elbows and knees), history of dry skin, onset under the age of two years, or personal history of asthma. There are slight adaptations for diagnostic criteria in children aged under four years. Childhood AE is very common, at some point affecting up to 20% of children aged five or under (Williams 2008). A systematic review of the epidemiology of AE however found that there is no specific overall global trend in the epidemiology of AE for either children or adults (Deckers 2012). Epidemiologic evidence of the disease for adults is less definitive. One study done in Japan suggests that only up to 3.3% of adults are affected by AE in their lifetime (Muto 2003). Nevertheless, the disease is often more chronic and severe in adults than in children (Herd 1996).

Impact

Atopic eczema causes significant distress in terms of discomfort and effect on appearance. In the case of children, the impact on the child and family is mainly due to sleep disturbance and itch (Chamlin 2004; Lewis‐Jones 1995). Research suggests that the impact of eczema on quality of life is second only to that of cerebral palsy, with greater impact reported for AE than for asthma or diabetes (Beattie 2006; Kemp 2003). Some of the many causes of treatment failure include the following: the fact that carers often do not use treatments correctly because of a lack of understanding of how they should be used, the refusal of children to allow carers to apply the treatment as prescribed, and the fact that the therapy can often be very time‐consuming (Beattie 2003). However, it should be noted that another major cause of treatment failure is the inherently persistent nature of AE itself. The disease also has a substantial impact on the lives of adolescents and adults. Atopic eczema has been described as a disease that causes cumulative life‐course impairment, which signifies that it impacts on a person's qualify of life in virtually all aspects and over the entire course of their lives, including in employment; personal relationships, such as familial ties; and mental health (Ibler 2013). Many of these disturbances are due to the social and psychological stigma associated with having a very visible skin disease (Ibler 2013). Sleep disturbance and itch also affects adults with AE (Bender 2003). The financial impact of AE on both the person and society also cannot be understated (Herd 2002).

Causes

Atopic eczema has many causes. The manner of development of the disease is still unclear. It is thought to include genetic predisposition, disturbed skin barrier function, and immunologic defects. Several studies suggest that there is an increased risk of developing AE in individuals with loss‐of‐function mutations in the filaggrin gene, which is present in up to 10% of western European populations (O'Regan 2009). Filaggrin is one of a number of structural proteins of the epidermis, which contribute to maintaining an effective skin barrier. Disturbances in skin barrier function facilitate greater penetration of allergens through the skin (Fallon 2009). It is thought that AE may be aggravated by contact with soaps or detergents, which can compromise the barrier function of the skin (Cork 2006). Protection of the skin barrier by excellent eczema care in early disease may decrease the risk of developing other atopic conditions (van den Oord 2009). It is important to note however that genetics and practices related to skin barrier protection alone do not explain the epidemiology of the disease: There is evidence that the environment, which can be influenced by socioeconomic and lifestyle factors, plays a role in AE (Williams 1995).

Description of the intervention

Many treatments are available for the management of AE in order to achieve satisfactory disease control. They have been classified into 10 groups (Hoare 2000). The initial approach to treating people requires basic therapy, which is focused on the use of hydrating topical treatments and the identification and avoidance of specific and non‐specific precipitating factors (Ring 2012). Topical application of corticosteroids is a cornerstone medical therapy for AE, followed by calcineurin inhibitors, such as pimecrolimus and tacrolimus (Boguniewicz 2008). Those with severe AE not responding to topical therapy require systemic therapy. Systemic pharmaceutical treatments include corticosteroids, antihistamines, antibiotics, cyclosporine, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, alitretinoin, intravenous immunoglobulins, interferon‐γ, monoclonal antibodies, and fusion proteins (Simon 2011). Phototherapy and photochemotherapy have also been used as conventional treatment options.

There has been a documented increase in the proportion of the general population who use Complementary and Alternative Medicine (CAM) for a variety of ailments in many countries, such as Korea (68.9%), France (49%), Germany (46%), United States (34%), Belgium (31%), UK (26%), and Sweden (25%) (Fisher 1994). More recently, one study suggested that there is a growing interest in CAM as a primary, maintenance, or simultaneous treatment for AE and demonstrated that there was a statistically significantly higher interest in treating AE with CAM interventions than psoriasis (Kim 2013), although epidemiological evidence of this kind for other parts of the world is lacking at this time.

Defining CAM is challenging, namely due to the fact that the field is not only very broad, encompassing dozens of disparate methods and practices from a variety of sociocultural contexts, but it is also constantly changing and evolving. The National Center for Complementary and Alternative Medicine (NCCAM), a centre of the National Institutes of Health in the United States, defines CAM as a "group of diverse medical and health care systems, practices and products that are not generally considered part of conventional medicine" (NCCAM 2013). Complementary and alternative medicine therapies represent "a group of therapeutic interventions that exist largely outside the institutions where conventional healthcare is taught and provided" (Zollman 1999). It has also been defined as "diagnosis, treatment or prevention which complements mainstream medicine by contributing to a common whole, by satisfying a demand not met by orthodoxy or by diversifying the conceptual frameworks of medicine" (Ernst 1995).

How the intervention might work

A total of 128 systematic reviews of variable quality have been conducted on all aspects of AE since the year 2000, demonstrating the interest of the scientific community in this topic (Futamura 2013). Of those, eight are Cochrane systematic reviews on CAM treatments for AE alone. These include published systematic reviews on Chinese herbal medicine (Gu 2013), dietary exclusions (Bath‐Hextall 2008), dietary supplements (Bath‐Hextall 2012), probiotics (Boyle 2008; Osborn 2007a), prebiotics (Osborn 2007), psychological and educational interventions (Ersser 2014), and oral evening primrose oil and borage oil (Bamford 2013), as well as a published protocol on specific allergen immunotherapy (Calderon 2010). Non‐Cochrane systematic reviews have also been published on some of these interventions (Ernst 2012; Foolad 2013; Simonart 2011).

However, not all CAM treatments have been reviewed. Acupuncture, aromatherapy, bath therapy, bioresonance, chromotherapy, homeopathy, hypnotherapy, massage therapy, phytotherapy, and relaxation techniques constitute some of the other CAM therapies that are known to be used for treating AE (Artik 2003). Yet, no Cochrane systematic review has been conducted on these interventions to date, despite their active use by people with AE. In this context, it appears to be of high importance to evaluate and critically appraise all CAM interventions used for AE that have not yet been reviewed, in order to assess their effect on AE. While this list is certainly not exhaustive, what follows is a brief description of some of the CAM interventions that have been used to treat AE but have not yet been the subject of a Cochrane systematic review.

Acupuncture

Acupuncture is a well‐known holistic treatment method that originated from eastern Asia but is now used in many other parts of the world. It consists of both needle and non‐needle treatments, although the former is more popularly associated with acupuncture than the latter. Non‐needle acupuncture is made up of many different methods, such as cupping, acupressure, and moxibustion (Chen 2003). In traditional eastern medicine, acupuncture needles are inserted at specific points "to stimulate, disperse, and regulate the flow of 'chi', or vital energy, and restore a healthy energy balance" (Cochrane CAM Field 2003). It is thought be potentially beneficial for those with a range of skin diseases, such as psoriasis, urticaria, and AE.

Aromatherapy

This therapy uses essential oils, distilled from plants, to treat emotional disorders, such as stress and anxiety, and a wide range of other ailments (Cochrane CAM Field 2003). In this CAM treatment, which is often used complementary with other non‐traditional therapies, such as acupuncture and herbology, various oils are administered to the body either via direct massage into the skin, inhalation, or distillation in baths.

Bath therapy

Baths or soaks (balneotherapy) involve immersing the skin in a variety of substances for the purpose of removing crusts or scales, washing away old medications, or alleviating itching and inflammation (Kubota 1997). They are useful for a variety of disorders involving large areas of the skin. By relieving dryness, inflammation, and itchiness of the skin, they can help reduce disease severity when used in combination with conventional topical antimicrobial treatment (Huang 2009).

Bioresonance

The theory behind this treatment assumes that "electromagnetic waves of the body can be conducted via external cables to an instrument that recognizes electromagnetic wave patterns, normalizes them, and then returns them to the patient via another electrode" (Artik 2003).

Chromotherapy

This involves the therapeutic use of colour, light, and relaxation techniques, which reduce the feelings of tension and the effects of stress.

Homeopathy

Homeopathy is a system of medicine in which the administration of specific chemical preparations to healthy participants produces similar manifestations of the disorder as seen in diseased individuals: This is known as the "similia principle" (Swayne 2000).

Massage therapy

Massage therapy includes a range of approaches rooted in both eastern and western healing practices. It involves the practice of "kneading or otherwise manipulating a person's muscles and other soft tissue with the intent of improving a person's well‐being or health" (Cochrane CAM Field 2003).

Phytotherapy

Phytotherapy consists of the use of plants, herbs, or plant extracts for medicinal purposes. Usually, the botanical extracts ‐ besides Chinese herbal medicine ‐ used for the treatment of AE are as follows: St John's wort (Hypericum perforatum); oolong tea; Arnica montana; calendula flowers; tea tree oil; German chamomile; Oregon grape root (Mahonia aquifolium); and a combination of Oregon grape, pansy (Viola tricolor), gotu kola (Centella asiatica), and liquorice (Glycyrrhiza glabra) (Torley 2013).

Relaxation techniques

This general term describes a variety of techniques that use Sequential Muscle Relaxation (SMR), meditation, yoga, breathing techniques, Qigong, Reiki, Shiatsu, and Tai chi to promote physical, mental, and spiritual well‐being. Some techniques induce relaxation or reduce pain, whereas others improve strength, and balance and treat emotional and mental distress (Cochrane CAM Field 2003).

Why it is important to do this review

According to the Global Burden of Disease study, AE is the most debilitating skin disease in the world, ahead of psoriasis, alopecia, and cellulitis (IMHE 2011), making it the most important dermatological disease to combat with respect to the quality of life of the world's population. It is a common, chronic inflammatory skin disease of both adults and children (Turner 2006; Williams 2005). Some CAM treatments, such as certain diets, evening primrose oil, homeopathy, hypnotherapy, and massage, are well known to be important sources of therapy sought by people with this condition (Bhuchar 2012). In essence, CAM can be broadly defined as a group of treatment methods that may be used either complementary or alternatively to conventional (i.e. western) medicine (NCCAM 2013). In fact, many people rely on these treatments as their primary tools to cure their illness or at least to improve the duration and quality of symptomatic relief. Yet, the clinical effectiveness of these interventions is often unclear. At the same time, it is evident that clinicians need to become more aware of the great variety of CAM treatments their patients are using to treat their illness (Bhuchar 2012). These issues are further compounded by the fact that the literature inconsistently represents the potential of these treatments to interact, both positively and negatively, with pharmacological agents, as well as to cause adverse effects even when used alone.

The parents of children with AE often feel that the disease is not taken sufficiently seriously by practitioners (Gore 2005) and wish for greater support from health services in dealing with their condition (Long 1993; Noerreslet 2009). Affected individuals are interested in pursuing non‐pharmacological approaches to AE management, such as exploring the role of diet, and they become frustrated when they perceive that their healthcare providers show little interest in these (Santer 2012). Clinicians are very much aware that people with AE often seek CAM therapies for clinical relief. Indeed, their patients may seek their advice on these treatments; yet, both clinicians and patients would benefit from greater clarity about the effectiveness of these interventions. Leading clinical journals, such as the Journal of the European Academy of Dermatology & Venereology, acknowledge the need for guidance on CAM treatments for AE, as shown by the recent publication of guidelines on this topic (NICE 2007; Ring 2012; Ring 2012a). Furthermore, there has been a tremendous proliferation of psychometrically tested outcomes tools for measuring the clinical improvements achieved with treatments for AE, with some tools shown to be more reliable and valid than others (Schmitt 2007).

Having thus reviewed the literature, we found no comprehensive, up‐to‐date, cohesive, and evidence‐based sources of information regarding the clinical effectiveness of CAM interventions for AE. In our review, we will seek to fill this knowledge gap by investigating the CAM treatments known to be used for AE that are not addressed by existing Cochrane systematic reviews that limited their research questions to the effectiveness of a single CAM intervention or class of interventions on AE.

Objectives

To assess the effects of complementary and alternative medicine treatments for atopic eczema.

Methods

Criteria for considering studies for this review

Types of studies

We will only consider randomised controlled trials (including parallel, cluster, within‐participant, and cross‐over randomised trials).

Types of participants

We will consider studies in which participants of any age, ethnicity, or gender had a clinically confirmed diagnosis of AE as evaluated by a qualified healthcare practitioner, as demonstrated by a clinical licence to diagnose and treat diseases, and based on either the UK Working Party, Hanifin and Rajka (Hanifin 1980), or explicitly stated provider‐based diagnostic criteria.

Types of interventions

We will define a CAM intervention as a treatment for AE that does not solely involve the use of a conventional, western medicine‐based, pharmaceutical preparation. This may include either one of the following:

• a treatment that is used as an alternative to conventional, western medicine‐based, pharmaceutical preparations; or

• a combination of a CAM treatment complementary to a traditional, western medicine‐based drug as the intervention.

These CAM treatments include, but are not limited to the following:

• acupuncture;

• aromatherapy;

• bath therapy;

• bioresonance;

• chromotherapy;

• homeopathy;

• massage therapy;

• phytotherapy; and

• relaxation techniques.

We will also consider studies that evaluated CAM treatments other than the ones listed here in people with AE. However, we cannot identify all of them a priori, given the wide scope of our review. Also, we will exclude the following list of CAM treatments as they are already the subject of other Cochrane systematic review projects: Chinese herbal medicine (Gu 2013), dietary exclusions (Bath‐Hextall 2008), dietary supplements (Bath‐Hextall 2012), probiotics (Boyle 2008; Osborn 2007a), prebiotics (Osborn 2007), psychological and educational interventions (Ersser 2014), oral evening primrose oil and borage oil (Bamford 2013), and specific allergen immunotherapy (Calderon 2010). We will consider all other CAM treatments that are used for AE.

The comparators of interest in this review must be as follows:

• an inactive treatment (such as placebo, observation, or no treatment);

• an active treatment (i.e. standard care, use of traditional pharmacologic interventions like corticosteroids and calcineurin inhibitors); or

• a combination of these two (i.e. waiting list control, time‐series controlled trials, or cross‐over designs).

Types of outcome measures

Given the presence of several tools for measuring patient‐centred outcomes for AE, we will place emphasis on studies that use at least one of these tools, as summarised in two comprehensive systematic reviews on these outcome measures (Schmitt 2007; Schmitt 2013). In particular, we will give studies that used objective outcome measures that can best capture clinical signs, such as the SCORing Atopic Dermatitis Index (SCORAD) or the Eczema Area and Severity Index (EASI), and subjective outcome measures that can best capture symptoms, such as the Patient Oriented Eczema Measure (POEM), greater consideration, as these tools have been identified as having the most robust performance in terms of psychometric properties (Schmitt 2013).

The SCORAD index is considered to be a valid, reliable, and objective outcomes instrument that appropriately captures the intensity and extent of clinical signs of AE, as well as the severity of the symptoms of the disease. The EASI tool is also thought to be a valid, reliable, and objective outcomes measure, but it focuses on clinical signs only and allows an assessment of the intensity of AE skin lesions at many sites on the body (Schmitt 2013). The POEM scale not only achieves good validity and reliability levels, but it also best captures what is important to the person with AE, by focusing entirely on the symptoms of the disease (Schmitt 2007).

Primary outcomes

1. Global improvement in objective AE outcomes as measured by SCORAD or EASI score or as reported by a clinician.

2. Global improvement in subjective AE outcomes as measured by the POEM score or as reported by participants.

3. Frequency of treatment discontinuation due to adverse effects.

Secondary outcomes

1. Proportion of participants with clinical clearance as assessed by a clinician.

2. Proportion of participants with 50% improvement in a given outcome as assessed by a clinician.

3. Time to relapse.

4. Type, frequency, and severity of adverse effects.

Search methods for identification of studies

We aim to identify all relevant randomised controlled trials (RCTs) regardless of language or publication status (published, unpublished, in press, or in progress).

Electronic searches

We will search the following databases for relevant trials:

• the Cochrane Skin Group Specialised Register;

• the Cochrane CAM Field Specialised Register;

• the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library;

• MEDLINE via OVID (from 1946);

• EMBASE via OVID (from 1974);

• AMED via OVID (Allied and Complementary Medicine Database) (from 1985);

• CINAHL via EBSCO (Cumulative Index to Nursing and Allied Health Literature, from 1981);

• The GREAT database (the Global Resource for EczemA Trials: www.greatdatabase.org.uk); and

• CAM‐QUEST.

We have devised a draft search strategy for RCTs for MEDLINE (OVID), which is shown in Appendix 1. We will use this as the framework for search strategies for the other databases listed.

Trials registers

We will search the following trials registers:

• The metaRegister of Controlled Trials (www.controlled‐trials.com).

• The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov).

• The Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).

• The World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch).

• The EU Clinical Trials Registry (www.clinicaltrialsregister.eu).

Searching other resources

Grey literature

We will contact investigators who have conducted RCTs on CAM interventions to obtain information about unpublished and ongoing studies pertinent to the review. We will contact members of the Cochrane CAM Field for assistance with this process.

Reference lists

We will check the bibliographies of all identified RCTs for further references to relevant trials.

Handsearching

We will not undertake any handsearching for this review, as we believe the planned search of databases and reference lists is comprehensive enough to capture all pertinent studies.

Adverse effects

We will not perform a separate search for adverse effects of the target interventions. However, we will examine data on adverse effects from the included studies we identify.

Special search considerations

While the interventions listed in this protocol reflect some commonly used CAM treatments for AE, we will not limit our systematic review to these interventions alone. Our goal is to assess the effect of CAM treatments that have not yet been the subject of a Cochrane systematic review. To achieve this goal, we will use a broad search strategy, as recommended by the Cochrane CAM Field, with very high sensitivity in order to retrieve all studies in which relevant CAM treatments were experimentally tested for patients with AE. The key words for the search strategy have been cross‐referenced with the glossary of known CAM interventions prepared by the Cochrane CAM Field, and additional key terms have been identified by discussion among all review authors.

Also, given that acupuncture is an intervention that is traditionally used in eastern Asia, we will search the five major Chinese biomedical databases (Xia 2008) for RCTs specifically related to acupuncture. We will attempt to include relevant non‐English language studies that are retrieved from the implementation of the broad search strategy. However, inclusion of these studies in the review will ultimately depend on the availability of external resources to support adequate translation into English.

Data collection and analysis

Selection of studies

We will identify and remove duplicate reports of studies, as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two review authors (MS and EV) will independently screen the studies against the inclusion criteria, first by title and abstract then by full review of the study report. We will resolve disagreements between these review authors via discussion or ultimately by consulting a third reviewer (GL). We will include 'Characteristics of excluded studies' tables, in which we will list the justifications for excluding studies based on full review of the articles.

Data extraction and management

Two review authors will independently extract data from the studies selected for inclusion in this review (YTJ and MS) and use these data to populate the 'Characteristics of included studies' tables. In studies with more than two intervention arms, we will only fully extract data for interventions that are relevant to this review; however, we will note the presence of the other interventions in the 'Characteristics of included studies' tables. As recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we will pilot test the data collection form on four studies selected for inclusion. We will resolve any disagreements between these reviewers via discussion or consultation with a third reviewer (EV). We will identify studies with multiple reports, and we will only select one of the reports to use to extract data for that study.

We will extract data as follows.

• General study information: full citation, publication status, declaration of interest of the investigators, and funding sources.

• Methodological characteristics: overall study design, type of trial (whether parallel, cluster, cross‐over, or within‐participant), total number of participants in each group, and duration of follow‐up period.

• Participant characteristics: diagnostic criteria used or method of diagnosis otherwise, sex, group demographics, and setting.

• Intervention characteristics: type of CAM treatment, dose, frequency, route and duration of administration, number of participants lost to follow up in each group, and whether the treatment was used as an alternative or a complement to traditional medical therapy and if so, name, dose, frequency, and route of administration of the said traditional treatment.

• Outcome data: time point and unit of measurement, and results for each outcome. For dichotomous outcomes, we will report the number of participants in each intervention group (n), as well as the total number of randomised participants per group (N). For continuous outcomes, we will report the mean, standard deviation (SD), and sample size of each group (N). For adverse events, we will extract the number, frequency, type, and site or organ involved in the body (cutaneous or otherwise).

Assessment of risk of bias in included studies

Two review authors will independently perform the 'Risk of bias' assessment (YTJ and GL) and resolve disagreement by discussion or consultation with a third reviewer (MS). We will use all domains of the 'Risk of bias' assessment tool as prescribed by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), including an evaluation of random sequence generation; allocation concealment; blinding of participants, investigators, personnel, and outcomes assessors; incomplete outcomes data; selective outcome reporting; and other biases.

Measures of treatment effect

We will express dichotomous outcomes as risk ratios (RR), and we will express continuous outcomes as mean differences (MD) and standardised mean differences (SMD) to allow for comparability of studies using different scales (SCORAD and EASI). We will report all outcomes results with a 95% confidence interval (CI).

Unit of analysis issues

We will follow the guidance of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) with regard to determination of the type of trial (parallel, cluster, cross‐over, or within‐participant) and how to handle the unit of analysis issues that subsequently result. We will meta‐analyse parallel trials using the inverse‐variance method. We will meta‐analyse cluster randomised studies preferably if they provide a direct estimate of the effect measure adjusted for the clustering effect. In the absence of this adjusted effect measure, we will conduct the meta‐analysis at the same level as the allocation, using a summary measurement from each cluster. We will include cross‐over trials only if sufficient data are available to allow for paired data to be included in a meta‐analysis via the inverse variance method without the need to impute data. For within‐participant studies where the participants received a different intervention at different sites of the body at the same time, we will use the same approach as for cross‐over trials. For within‐participant studies where the participants received the same intervention at different sites of the body at the same time, we will use the same approach as for cluster randomised trials. We will not use data imputation to deal with any unit of analysis issues.

Dealing with missing data

We will make two separate electronic attempts to retrieve missing data from the study authors. We will exclude from the meta‐analysis altogether studies containing data that appear to be missing not at random and that cannot be retrieved from the authors within one month. If we cannot retrieve data that appear to be missing at random from the study authors within one month, we will examine the available data using an available case analysis approach and include them in the meta‐analysis where possible.

Assessment of heterogeneity

We will use visual inspection to determine whether or not there appears to be too great a degree of between‐study heterogeneity to justify performing a meta‐analysis. If the latter appears justified, we will use the I² statistic to quantify the proportion of heterogeneity related to between‐study variation rather than chance. As recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we will consider I² statistic values greater than 50% as suggestive that there is substantial heterogeneity. In these instances, we will not perform a meta‐analysis, and we will present the results narratively. We will not pool into a meta‐analysis studies that demonstrate substantial clinical heterogeneity where there are evident differences between participants, interventions, or outcomes.

Assessment of reporting biases

We will check for the presence of reporting bias using funnel plots if at least 10 studies are available for inclusion in the meta‐analysis.

Data synthesis

We will pool separately studies that use the same CAM intervention in an alternative format and those that use it in a complementary format, as we consider these to be two separate interventions. Given the eclectic nature of CAM treatment and the likely difficulty of replicating CAM interventions in the same way across studies, we believe that the random‐effects method is more appropriate to perform the meta‐analyses for outcomes where the I² statistic is less than 50%. We will report in a tabular format outcomes data from studies that cannot be pooled into a meta‐analysis (I² statistic greater than 50% or data that are not missing at random).

We plan to include at least one 'Summary of findings' table in the review. In this table, we will summarise the primary outcomes for the most important comparison. If we feel there are several major comparisons or that our findings need to be summarised for different populations, we will include further 'Summary of findings' tables. We will use the five GRADE considerations (study limitations, consistency of effects, imprecision, indirectness, and publication bias) to evaluate the overall quality of the evidence for each outcome of interest in our review. We will document the steps we take in the review in upgrading or downgrading the body of evidence, and we will make conclusions on the basis of this evaluation of the quality of the evidence.

Subgroup analysis and investigation of heterogeneity

We believe that limiting the search to studies that only used the UK Working Party diagnostic criteria would potentially eliminate a large number of otherwise high‐quality studies of CAM treatments for AE. To address this issue and if at least 10 studies are available for the given outcome, we will perform a subgroup analysis by type of diagnostic criteria, including the UK Working Party, Hanifin and Rajka (Hanifin 1980), or provider‐based criteria, to assess if any significant differences exist between studies with different diagnostic criteria for AE, particularly if there is evidence of significant between‐study heterogeneity. We will also perform subgroup analyses by type of objective outcomes tool used (SCORAD or EASI) and by type of trial (parallel, cluster, cross‐over, or within‐participant), to determine whether these variables have an impact on the overall effect size. We will use meta‐regression to evaluate the statistical significance of differences in effects between subgroups.

Sensitivity analysis

We will conduct sensitivity analyses by excluding studies with a high risk of bias within a particular category of risk of bias (selection, performance, detection, attrition, and reporting), in order to determine whether these factors influence the interpretation of the meta‐analysis. We will also perform a sensitivity analysis to determine the extent to which our approach to dealing with missing data has an impact on the effect size and interpretation of the meta‐analysis, and if more than 10 studies are available, we will use meta‐regression to assess the role of the degree of missing data on the effect size. We will follow the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) for this purpose.

Appendices

Appendix 1. MEDLINE (OVID) search strategy

1. randomized controlled trial.pt. 2. controlled clinical trial.pt. 3. randomized.ab. 4. placebo.ab. 5. clinical trials as topic.sh. 6. randomly.ab. 7. trial.ti. 8. 1 or 2 or 3 or 4 or 5 or 6 or 7 9. exp animals/ not humans.sh. 10. 8 not 9 11. exp Eczema/ or eczema.mp. 12. exp Dermatitis, Atopic/ 13. neurodermatitis.mp. or exp Neurodermatitis/ 14. exp Dermatitis/ or dermatitis.mp. 15. or/11‐14 16. acoustic stimulation.mp. or exp Acoustic Stimulation/ 17. acupressure.mp. or exp Acupressure/ 18. exp Acupuncture/ or acupuncture.mp. 19. exp Medicine, African Traditional/ 20. anthroposophy.mp. or exp Anthroposophy/ 21. antioxidants.mp. or exp Antioxidants/ 22. arabic medicine.mp. or exp Medicine, Arabic/ 23. aromatherapy.mp. or exp Aromatherapy/ 24. art therapy.mp. or exp Art Therapy/ 25. auricular therapy.mp. 26. exp Medicine, Ayurvedic/ 27. ayurved$.mp. 28. biofeedback.mp. or exp Biofeedback, Psychology/ 29. breathing exercise$.mp. or exp Breathing Exercises/ 30. exp Color Therapy/ 31. (color therap$ or colour therap$).mp. 32. exp complementary therapies/ or exp acupuncture therapy/ or exp anthroposophy/ or exp auriculotherapy/ or exp holistic health/ or exp homeopathy/ or exp horticultural therapy/ or exp medicine, traditional/ or exp mesotherapy/ or exp mind‐body therapies/ or exp musculoskeletal manipulations/ or exp naturopathy/ or exp organotherapy/ or exp phytotherapy/ or exp reflexotherapy/ or exp rejuvenation/ or exp sensory art therapies/ or exp speleotherapy/ or exp spiritual therapies/ 33. dance therapy.mp. or exp Dance Therapy/ 34. exp Medicine, East Asian Traditional/ 35. eclecticism.mp. or exp Eclecticism, Historical/ 36. electroacupuncture.mp. or exp Electroacupuncture/ 37. faith healing.mp. or exp Faith Healing/ 38. holistic health.mp. 39. homeopathy.mp. 40. horticultural therapy.mp. 41. hypnosis.mp. or exp Hypnosis/ 42. exp "Imagery (Psychotherapy)"/ 43. kampo.mp. or exp Medicine, Kampo/ 44. exp Kinesiology, Applied/ or kinesiology.mp. 45. laughter therapy.mp. or exp Laughter Therapy/ 46. magic.mp. or exp Magic/ 47. manipulation.mp. or exp Manipulation, Chiropractic/ 48. exp Massage/ or massage.mp. 49. meditation.mp. or exp Meditation/ 50. mental healing.mp. or exp Mental Healing/ 51. mesotherapy.mp. or exp Mesotherapy/ 52. moxibustion.mp. or exp Moxibustion/ 53. music therapy.mp. or exp Music Therapy/ 54. exp Naturopathy/ or naturopath$.mp. 55. natural remed$.mp. 56. occultism.mp. or exp Occultism/ 57. exp Psychodrama/ or psychodrama.mp. 58. drama therapy.mp. 59. Psychology/ or psychology.mp. 60. psychophysiology.mp. or exp Psychophysiology/ 61. mind body relation$.mp. 62. radiesthesia.mp. or exp Radiesthesia/ 63. reflexotherapy.mp. or exp Reflexotherapy/ 64. rejuvenation.mp. or exp Rejuvenation/ 65. relaxation therapy.mp. or exp Relaxation Therapy/ 66. shamanism.mp. or exp Shamanism/ 67. speleotherapy.mp. or exp Speleotherapy/ 68. Tai Ji/ 69. tai chi.mp. 70. therapeutic touch.mp. or exp Therapeutic Touch/ 71. exp Medicine, Unani/ or unani.mp. 72. witchcraft.mp. or exp Witchcraft/ 73. yoga.mp. or exp Yoga/ 74. visualisation.mp. 75. immunoaugmentation.mp. 76. Tissue Therapy/ 77. Medicine, Chinese Traditional/ 78. tcm.mp. 79. antineoplaston.mp. 80. chelation.mp. 81. shark.mp. 82. electromagnetic$.mp. 83. "Tea Tree Oil"/ 84. Aloe/ 85. reflexology.mp. 86. reiki.mp. 87. herb$.mp. 88. physical therapy.mp. 89. cupping therapy.mp. 90. therapeutic exercise.mp. 91. folk.mp. 92. bioelectromagnetic$.mp. 93. Diet/ 94. nutrition.mp. 95. Diet, Macrobiotic/ 96. gerson.mp. 97. support group.mp. or Self‐Help Groups/ 98. electrical stimulation.mp. or exp Electric Stimulation/ 99. laser therapy.mp. or exp Laser Therapy/ 100. tuina.mp. 101. qigong.mp. or exp Breathing Exercises/ 102. alexander technique.mp. 103. bioenergetics.mp. or exp Energy Metabolism/ 104. exp Chiropractic/ or chiropractic.mp. 105. cranisacral therapy.mp. 106. deep tissue bodywork.mp. 107. energy field work.mp. 108. feldenkrais.mp. 109. flower essence$.mp. 110. exp Plant Extracts/ 111. exp Plant Preparations/ 112. gestalt therapy.mp. or exp Gestalt Therapy/ 113. exp Therapeutic Touch/ or healing touch.mp. 114. herbalism.mp. 115. exp Herbal Medicine/ 116. hypnotherapy.mp. 117. magnets.mp. 118. myofacial release.mp. 119. nursing holistic.mp. or exp Holistic Nursing/ 120. osteopathic medicine.mp. or exp Osteopathic Medicine/ 121. shiatsu.mp. or exp Acupressure/ 122. structural integration.mp. 123. trigger point myotherapy.mp. 124. zero balancing.mp. 125. Nambudripad's Allergy Elimination Technique.mp. 126. NAET.mp. 127. or/16‐126 128. 10 and 15 and 127

What's new

Date	Event	Description
11 September 2017	Amended	The authors have requested this protocol to be withdrawn. They have relinquished responsibility for this protocol. It was published several years ago, and Cochrane Skin have decided to withdraw it (Managing Editor, Cochrane Skin).

Contributions of authors

YTJ was the contact person with the editorial base. YTJ co‐ordinated the contributions from the co‐authors and wrote the final draft of the protocol. YTJ and DG worked on the methods sections. EV and MS drafted the clinical sections of the background and responded to the clinical comments of the referees. YTJ and DG responded to the methodology and statistics comments of the referees. All authors contributed to writing the protocol. KM was the consumer co‐author and checked the protocol for readability and clarity. He also ensured that the outcomes are relevant to consumers. YTJ is the guarantor of the final review.

Disclaimer

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health, UK.

Sources of support

Internal sources

• No sources of support supplied

External sources

• The National Institute for Health Research (NIHR), UK.

  The NIHR, UK, is the largest single funder of the Cochrane Skin Group.

Declarations of interest

Dr Vakirlis Efstratios: "I have received lecture honoraria from MEDA Pharmaceutical as invited speaker for atopic dermatitis."

Notes

The authors have requested this protocol to be withdrawn. They have relinquished responsibility for this protocol. It was published several years ago, and Cochrane Skin have decided to withdraw it (Managing Editor, Cochrane Skin).

Withdrawn from publication for reasons stated in the review