Strategies for using topical corticosteroids in children and adults with eczema

Authors: Stephanie J Lax, Jane Harvey, Emma Axon, Laura Howells, Miriam Santer, Matthew J Ridd, Sandra Lawton, Sinéad Langan, Amanda Roberts, Amina Ahmed, Ingrid Muller, Long Chiau Ming, Saumya Panda, Pavel Chernyshov, Ben Carter, Hywel C Williams, Kim S Thomas, Joanne R Chalmers

Abstract

Background

Eczema is a common skin condition. Although topical corticosteroids have been a first‐line treatment for eczema for decades, there are uncertainties over their optimal use.

Objectives

To establish the effectiveness and safety of different ways of using topical corticosteroids for treating eczema.

Search methods

We searched databases to January 2021 (Cochrane Skin Specialised Register; CENTRAL; MEDLINE; Embase; GREAT) and five clinical trials registers. We checked bibliographies from included trials to identify further trials.

Selection criteria

Randomised controlled trials in adults and children with eczema that compared at least two strategies of topical corticosteroid use. We excluded placebo comparisons, other than for trials that evaluated proactive versus reactive treatment.

Data collection and analysis

We used standard Cochrane methods, with GRADE certainty of evidence for key findings. Primary outcomes were changes in clinician‐reported signs and relevant local adverse events. Secondary outcomes were patient‐reported symptoms and relevant systemic adverse events. For local adverse events, we prioritised abnormal skin thinning as a key area of concern for healthcare professionals and patients.

Main results

We included 104 trials (8443 participants). Most trials were conducted in high‐income countries (81/104), most likely in outpatient or other hospital settings. We judged only one trial to be low risk of bias across all domains. Fifty‐five trials had high risk of bias in at least one domain, mostly due to lack of blinding or missing outcome data.

Stronger‐potency versus weaker‐potency topical corticosteroids

Sixty‐three trials compared different potencies of topical 12 moderate versus mild, 22 potent versus mild, 25 potent versus moderate, and 6 very potent versus potent. Trials were usually in children with moderate or severe eczema, where specified, lasting one to five weeks. The most reported outcome was Investigator Global Assessment (IGA) of clinician‐reported signs of eczema.

We pooled four trials that compared moderate‐ versus mild‐potency topical corticosteroids (420 participants). Moderate‐potency topical corticosteroids probably result in more participants achieving treatment success, defined as cleared or marked improvement on IGA (52% versus 34%; odds ratio (OR) 2.07, 95% confidence interval (CI) 1.41 to 3.04; moderate‐certainty evidence). We pooled nine trials that compared potent versus mild‐potency topical corticosteroids (392 participants). Potent topical corticosteroids probably result in a large increase in number achieving treatment success (70% versus 39%; OR 3.71, 95% CI 2.04 to 6.72; moderate‐certainty evidence). We pooled 15 trials that compared potent versus moderate‐potency topical corticosteroids (1053 participants). There was insufficient evidence of a benefit of potent topical corticosteroids compared to moderate topical corticosteroids (OR 1.33, 95% CI 0.93 to 1.89; moderate‐certainty evidence). We pooled three trials that compared very potent versus potent topical corticosteroids (216 participants). The evidence is uncertain with a wide confidence interval (OR 0.53, 95% CI 0.13 to 2.09; low‐certainty evidence).

Twice daily or more versus once daily application

We pooled 15 of 25 trials in this comparison (1821 participants, all reported IGA). The trials usually assessed adults and children with moderate or severe eczema, where specified, using potent topical corticosteroids, lasting two to six weeks.

Applying potent topical corticosteroids only once a day probably does not decrease the number achieving treatment success compared to twice daily application (OR 0.97, 95% CI 0.68 to 1.38; 15 trials, 1821 participants; moderate‐certainty evidence).

Local adverse events

Within the trials that tested 'treating eczema flare‐up' strategies, we identified only 26 cases of abnormal skin thinning from 2266 participants (1% across 22 trials). Most cases were from the use of higher‐potency topical corticosteroids (16 with very potent, 6 with potent, 2 with moderate and 2 with mild). We assessed this evidence as low certainty, except for very potent versus potent topical corticosteroids, which was very low‐certainty evidence.

Longer versus shorter‐term duration of application for induction of remission

No trials were identified.

Twice weekly application (weekend, or ‘proactive therapy') to prevent relapse (flare‐ups) versus no topical corticosteroids/reactive application

Nine trials assessed this comparison, generally lasting 16 to 20 weeks. We pooled seven trials that compared weekend (proactive) topical corticosteroids therapy versus no topical corticosteroids (1179 participants, children and adults with a range of eczema severities, though mainly moderate or severe).

Weekend (proactive) therapy probably results in a large decrease in likelihood of a relapse from 58% to 25% (risk ratio (RR) 0.43, 95% CI 0.32 to 0.57; 7 trials, 1149 participants; moderate‐certainty evidence).

Local adverse events

We did not identify any cases of abnormal skin thinning in seven trials that assessed skin thinning (1050 participants) at the end of treatment. We assessed this evidence as low certainty.

**Other comparisons **

Other comparisons included newer versus older preparations of topical corticosteroids (15 trials), cream versus ointment (7 trials), topical corticosteroids with wet wrap versus no wet wrap (6 trials), number of days per week applied (4 trials), different concentrations of the same topical corticosteroids (2 trials), time of day applied (2 trials), topical corticosteroids alternating with topical calcineurin inhibitors versus topical corticosteroids alone (1 trial), application to wet versus dry skin (1 trial) and application before versus after emollient (1 trial). No trials compared branded versus generic topical corticosteroids and time between application of emollient and topical corticosteroids.

Authors' conclusions

Potent and moderate topical corticosteroids are probably more effective than mild topical corticosteroids, primarily in moderate or severe eczema; however, there is uncertain evidence to support any advantage of very potent over potent topical corticosteroids. Effectiveness is similar between once daily and twice daily (or more) frequent use of potent topical corticosteroids to treat eczema flare‐ups, and topical corticosteroids weekend (proactive) therapy is probably better than no topical corticosteroids/reactive use to prevent eczema relapse (flare‐ups). Adverse events were not well reported and came largely from low‐ or very low‐certainty, short‐term trials. In trials that reported abnormal skin thinning, frequency was low overall and increased with increasing potency. We found no trials on the optimum duration of treatment of a flare, branded versus generic topical corticosteroids, and time to leave between application of topical corticosteroids and emollient. There is a need for longer‐term trials, in people with mild eczema.

Summary of findings

Background

Description of the condition

Eczema (also called 'atopic dermatitis' or 'atopic eczema') is a chronic inflammatory skin condition, characterised by dry skin with itchy patches, which typically fluctuates between periods of remission and flares. Eczema often occurs concurrently with atopic diseases including asthma, allergic rhinitis/hay fever and food allergy. These diseases share a common pathogenesis, and frequently present together in the same individual and family. 'Atopy' refers to the genetic tendency to produce immunoglobulin E (IgE;  Table 8 for abbreviations) antibodies in response to small amounts of common environmental proteins such as pollen, house dust mite, and food allergens (Stone 2002; Thomsen 2015). Around 30% of people with eczema develop asthma and 35% develop allergic rhinitis (Luoma 1983). However, it is known that atopy does not concurrently occur in all people with atopic eczema. In view of this, there have been recent proposals to use the term 'eczema' to define people both with and without atopy. In agreement with the 'Revised nomenclature for allergy for global use' (Johansson 2004), and for consistency with other Cochrane Reviews that evaluate eczema therapies (Van Zuuren 2017), we will use the term 'eczema' throughout the review.

Eczema is a common condition throughout the world affecting approximately one in five children, and up to 5% of adults (Barbarot 2018; Odhiambo 2009). The incidence of eczema is highest in the first year of life and can often resolve during childhood (Ban 2018; Kim 2016). However, a recent review has shown that persistence into adolescence and early adulthood may be more common than previously thought, particularly for those with persistent and severe disease or late onset disease (Abuabara 2018).

Eczema can have a significant impact on quality of life (Eckert 2017); and there is a high burden associated with eczema when compared to other skin diseases (Hay 2014). Both the individual and their family can be affected by the disease through factors including disturbed sleep due to itching and scratching, time off work or school for frequent visits to healthcare professionals, restrictions to daily activities, and the need to apply daily, time‐consuming treatments (Drucker 2016; Eckert 2018).

Clinical features

Eczema may be acute (short and severe) with weeping vesicles on red, swollen skin, or it may be chronic (long‐term) with inflammation, lichenification (thickening of the skin caused by repeated rubbing or scratching), excoriation (abrasion because of rubbing or scratching), hyperpigmentation, and exaggerated surface markings (Weidinger 2016). The typical distribution and type of lesions vary during different stages of life and between different ethnicities. In infants, the extremities and face are usually affected. By around two years of age, lesions mainly appear on the limbs, particularly in the creases of the elbows and knees, as well as the neck, wrists, and ankles. In adulthood, the lesions can become more widespread than those seen in childhood (Bieber 2008a).

The severity of eczema can vary enormously, ranging from dry skin with the occasional itchy inflamed patch, to involvement of the whole body with secondary infections. The course of eczema may also vary from a relapsing‐remitting one affecting a few areas recurrently to a continuous one with prolonged periods of inflamed skin covering most of the body (Berke 2012). Itching can induce a vicious cycle of scratching, leading to skin damage, which in turn causes itchiness—often referred to as the 'itch‐scratch cycle' (Pavlis 2017).

Treatment of eczema

There is currently no cure for eczema, so the treatment goal is control of the disease using the wide range of treatments available including emollients (NICE 2007; SIGN 2011). First‐line therapy is the daily application of emollients combined with anti‐inflammatory therapy. The most commonly used anti‐inflammatory therapy is topical corticosteroids, but topical calcineurin inhibitors are also used. These can be combined with bandages and phototherapy for those who do not respond sufficiently to topical treatment alone. Severe eczema may require systemic treatments such as oral ciclosporin, methotrexate or azathioprine. New biologic agents such as dupilumab are now available for cases of eczema that do not respond to other systemic treatments (Snast 2018). Although topical corticosteroids have been the mainstay of eczema treatment for over 60 years, there are still many unanswered questions about how best to use them (Batchelor 2013).

Description of the intervention

Topical corticosteroids were first introduced in the 1950s when topical hydrocortisone was found to improve various dermatoses (Sulzberger 1952). Since then, a huge number of topical corticosteroids of increased potency have been developed, and are available in various formulations such as creams and ointments. Mometasone furoate is one of the newer generation of products developed with the intention of producing a safer, potent topical corticosteroid (Prakash 1998). Topical corticosteroids are all classified by their potency from mild through to very potent, although the classification of potency varies around the world (British National Formulary 2018; WHO 1997). The choice of potency to be used is based on age, body site to be treated and severity of eczema. Low‐ to moderate‐potency topical corticosteroids are usually sufficient for mild eczema and are also used on sensitive skin such as the face and flexural areas. Potent or very potent topical corticosteroids are usually used in severe, thick eczematous plaques over thicker skin sites, such as limbs and palmoplantar surfaces. The advice is to use topical corticosteroids, of appropriate potency, once a day until the eczema is controlled, then 'as required' (NICE 2007).

Local side effects of topical corticosteroids include the possibility of skin atrophy (skin thinning), striae (stretch marks) and purpura (discolouration). To a degree, thinning can be a desirable effect of topical corticosteroid use in restoring abnormally thickened eczematous skin. Abnormal skin thinning, however, can lead to bruising, tearing, and small blood vessels becoming more visible. It has been reported that the skin can recover once topical corticosteroids are stopped (Eichenfield 2014b). Systemic side effects include hypothalamic pituitary axis suppression and growth suppression (Callen 2007). Skin thinning and effects on growth and development have been reported to be the main concerns amongst people using topical corticosteroids (Li 2017). Side effects of topical corticosteroids are thought to be rare in usual practice and are more likely to occur if topical corticosteroids have been used inappropriately, such as continuous use or if potent corticosteroids are applied to areas with high permeability, such as eyelids (Callen 2007; Nankervis 2016). This inappropriate use could lead to systemic side effects such as hypothalamic pituitary axis suppression or hyperglycaemia (Gilbertson 1998). But, despite their relative safety, concerns and confusion about the use of topical corticosteroids amongst people with eczema and the healthcare professionals who treat them are widespread. Negative beliefs about the use of topical corticosteroids are thought to contribute to poor treatment adherence (Aubert‐Wastiaux 2011; Li 2017; Teasdale 2017).

How the intervention might work

Topical corticosteroids have traditionally been used reactively (in response to a worsening of the eczema) to control inflammation under the skin. They work by reducing skin inflammation by acting on a number of inflammatory pathways. They bind to glucocorticoid intracellular receptors, which then results in a number of anti‐inflammatory actions. These include inhibition of phospholipase A2 activity, resulting in reduced production of lipid mediators; inhibition of cyclo‐oxygenase induction, causing decreased prostaglandin production; inhibition of nitric oxide synthase production; inhibition of cytokine, causing suppression of cell‐mediated inflammation; inhibition of mast cell activity, resulting in decreased levels of mast cell inflammatory mediators; and vasoconstriction (local blood flow reduction; Ahluwalia 1998).

A number of different ways (or 'strategies') of using topical corticosteroids for treating eczema have been proposed. Proactive use of topical corticosteroids for two days per week between flares is thought to help to prevent eczema flares and therefore reduce the need for more intense periods of topical corticosteroid use to treat flares, which may be associated with an increase in adverse events (Schmitt 2011). Applying topical corticosteroids to wet skin after bathing or use of wet wraps may increase penetration through the skin and increase delivery of the cream or ointment into the upper layers, thus increasing efficacy of the topical corticosteroid (González‐López 2017; Kohn 2016). Topical calcineurin inhibitors (pimecrolimus or tacrolimus) can be used instead of topical corticosteroids and a strategy of alternating between these two treatments may be as effective as using topical corticosteroids alone, but may reduce the adverse events associated with topical corticosteroids, such as skin thinning (Broeders 2016).

Some strategies aim to reduce adverse events whilst increasing or maintaining effectiveness of the topical corticosteroid. Applying topical corticosteroids once daily may be as effective as two or more times a day but may reduce the likelihood of adverse events occurring (Green 2004). Another strategy Is to use different potency topical corticosteroids, possibly combined with different duration of use, such as a more potent topical corticosteroid for a shorter period compared to milder potency topical corticosteroids for a longer duration. This reduces the length of time the topical corticosteroid would be used although more potent topical corticosteroids may be associated with increased adverse events (Thomas 2002).

Since topical corticosteroids are used with emollients, other proposed strategies concern the combined use of these two treatments, such as the order in which the treatments are applied and the optimum time lapse between application of each treatment. Current guidance in the UK from the National Health Service (NHS) is to apply emollients first then wait for 30 minutes before applying the topical corticosteroid for maximal benefit (NHS 2019). Additionally, different preparations of topical corticosteroids (e.g. ointments, creams) have been developed to increase the efficacy; and different concentrations (e.g. hydrocortisone 0.5% versus 2.5%). More recently, 'second‐generation' once daily topical corticosteroids (mometasone furoate and fluticasone propionate) have been proposed as a safer and effective alternative to the older topical corticosteroid preparations (Bieber 2008b).

Why it is important to do this review

It is well established that some patients, parents and clinicians have considerable concerns about using topical corticosteroids for treating eczema (Charman 2000; Li 2017; Teasdale 2017). As a result, topical corticosteroids are often under‐used in Western countries, resulting in poorly controlled disease (Lundin 2018). Conversely, in other areas of the world, such as India, potent topical corticosteroid use is often unregulated and patients are able to obtain these steroids over the counter. Subsequent inappropriate use of potent topical corticosteroids can lead to an increase in adverse events (Coondoo 2014).

This situation is exacerbated by the lack of clarity as to how the different ways of using topical corticosteroids — such as once‐a‐day or twice‐a‐day application, increasing topical corticosteroid potency in response to a flare, or twice‐a‐week use to proactively prevent flares — affect both effectiveness and safety profile. The British National Formulary (BNF) provides little reassurance, describing adrenal suppression as rare but providing no quantification of other side effects (British National Formulary 2018). Concerns and uncertainties around topical corticosteroids were highlighted in the James Lind Alliance Priority Setting Partnership for eczema, in which the following two topics relating to topical corticosteroid safety were identified by patients and healthcare professionals as priority areas for research (Batchelor 2013).

“What is the best and safest way of using topical corticosteroids?”“What is the long‐term safety of topical corticosteroids?”

This comprehensive systematic review is needed to summarise the available evidence on the effectiveness and safety of different ways of using topical corticosteroids to support patients and clinicians in making informed treatment choices. However, since most eczema trials have a relatively short follow‐up, this review will primarily address the first of these two questions.

The strategies included in this review will refer to different methods of using topical corticosteroids to improve effectiveness or safety, or both, and hence achieve the best outcomes for patients. A strategy may aim to improve the long‐term control of eczema, for example, in the case of proactive topical corticosteroid treatment. This strategy involves weekly application of topical corticosteroid, for two consecutive days, to previously affected or new sites of eczema, to reduce the risk of flares (Schmitt 2011). Alternatively, a strategy such as reducing the frequency of application may be designed to improve the safety of the drug whilst maintaining effectiveness (Green 2004; Williams 2007).

This review forms part of a body of work funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research (grant RP‐PG‐0216‐20007) to develop an online behavioural intervention to support self‐care of eczema in children, adolescents and young adults (Eczema Care Online, ECO), and the findings will contribute to development of the intervention by providing data on the best and safest ways to use topical corticosteroids.

This review will be complemented by another ongoing Cochrane Review, which will incorporate a network meta‐analysis: 'Topical treatments for a network meta‐analysis' The ongoing Cochrane Review will compare topical corticosteroids to other topical treatments, such as topical calcineurin inhibitors.

Objectives

To establish the effectiveness and safety of different ways of using topical corticosteroids in people with eczema.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) where randomisation is at any level (including cluster and within‐participant trials).

Types of participants

Participants of any age and gender with a diagnosis of eczema (also known as atopic dermatitis or atopic eczema) of any severity by a healthcare professional, or using established diagnostic criteria for eczema, e.g., the standardised diagnostic criteria of Hanifin and Rajka (Hanifin 1980) or the UK Working Party diagnostic criteria for atopic dermatitis (Williams 1994). We also accepted modified versions of standard diagnostic criteria. Where it was unclear whether a trial included participants with atopic eczema, a senior clinician (HCW) made a judgement as to whether the trial was to be included. This was primarily based upon the pattern of symptoms described in the paper.

We included trials that included participants with other types of eczema such as contact dermatitis, varicose eczema, and seborrhoeic eczema, or other inflammatory or 'steroid‐responsive' skin conditions such as psoriasis, only if the trial also included people with eczema and the data were reported separately.

Types of interventions

The intervention was any topical corticosteroid of any preparation and potency in a trial where one strategy of using the topical corticosteroid was compared to a different strategy. This included the following strategies (see Figure 1).

Which topical corticosteroid to use?

Stronger‐potency topical corticosteroid versus weaker‐potency topical corticosteroidModerate‐ versus mild‐potency topical corticosteroidPotent versus mild‐potency topical corticosteroidPotent versus moderate‐potency topical corticosteroidVery potent versus potent topical corticosteroidTopical corticosteroid cream versus topical corticosteroid ointmentDifferent concentrations of the same topical corticosteroidSecond‐generation topical corticosteroid (mometasone furoate and fluticasone propionate) versus older topical corticosteroidBranded topical corticosteroid versus generic topical corticosteroid

How often to apply topical corticosteroid?

Twice or more versus once daily application of topical corticosteroidDaily application versus less frequent application per weekLonger‐ (more than seven days) versus shorter‐term (7 days) duration of use for induction of remissionTopical corticosteroid alternating with topical calcineurin inhibitor versus topical corticosteroid aloneWeekend therapy (proactive topical corticosteroid) versus no proactive topical corticosteroid (e.g. twice per week versus 'as required')

How to use the topical corticosteroid?

Timing of application of topical corticosteroidWet wrap versus no wet wrapTopical corticosteroid applied to wet versus dry skinTopical corticosteroid applied before emollient versus topical corticosteroid applied after emollientTime between application of emollient and steroid

We also included combinations of any of the strategies above (e.g. short burst of potent topical corticosteroids versus longer duration of mild topical corticosteroids).

Since the focus of this review was to compare different strategies of using topical corticosteroids, we excluded the following comparisons.

Topical corticosteroid compared with either no treatment, vehicle or placebo (unless it was specifically assessing an alternative regimen such as weekend (proactive) therapy)Topical corticosteroid compared with another topical corticosteroid of the same potency and preparation but no differences in how they were used. We developed a hierarchy of sources to assign potency to each topical corticosteroid (Table 9). Potencies were most frequently determined using the British National Formulary 2018 and WHO 1997. If we could not establish the potency using these sources, we reviewed regional guidelines and the wider scientific literature, and consulted regional experts until we could reach a decision.Topical corticosteroid compared with different topical treatments such as calcineurin inhibitors or emollientsTopical corticosteroid compared with systemic treatmentsTopical corticosteroid treatment in conjunction with an eczema treatment used for the most severe cases of eczema as defined by The National Institute for Health and Care Excellence (NICE); that is, phototherapy and systemic therapy (NICE 2018). This was because it would have been difficult to detect any differences in efficacy or safety between the topical corticosteroid strategies when such treatments were also used.

Types of outcome measures

We assessed both effectiveness and safety to reflect the overall aim of this review.

The effectiveness outcomes of interest for this review were focused on the two domains for which the international Harmonizing Outcome Measures for Eczema (HOME) initiative recommended core outcome measurement instruments, that is, clinician‐reported signs and patient‐reported symptoms of eczema (HOME).

There is currently no agreed standardised timing for effectiveness outcome assessments for eczema trials. Therefore, to assess treatment effects in a consistent way, we focused on short‐term effectiveness outcomes reported between one and four weeks (taking the earliest available time point within that range), medium‐term effectiveness outcomes between 12 and 16 weeks (taking the closest time point to 12 weeks), and long‐term effectiveness as the longest time point longer than 16 weeks.

We also reported outcomes at baseline, end of treatment, and end of follow‐up regardless of timing. We attempted to pool data at similar time points where possible.

Because many different instruments are used to assess effectiveness of treatments for eczema (Schmitt 2007), we used a hierarchical approach in which we initially extracted data from one instrument per outcome based on the priority order described below. We also made a note of the other instruments reported to maximise our ability to summarise data in pooled analyses of lower‐priority instruments. We planned to compare effect sizes against minimal clinically important differences (MCID) from the literature where possible.

Throughout this review, we used the term 'effectiveness' to describe both 'efficacy' and 'effectiveness'. In many trials it was unclear whether the trial was primarily assessing efficacy or effectiveness and we preferred to avoid making inappropriate judgements.

Safety outcomes of interest reflected the side effects of topical corticosteroids. We defined 'relevant' adverse events as those previously identified as being of particular concern to patients (Li 2017), the side effects listed in the Summary of Product Characteristics for topical corticosteroids used to treat eczema, and original data submissions from the Eczema Priority Setting Partnership, outlining patients' and clinicians' concerns about the safety of topical corticosteroids (Batchelor 2013). We reported data on individual relevant adverse events and their relatedness to the trial drug where available. Where outcomes were assessed during post‐treatment follow‐up, we only included data where participants are retained in their randomised groups. We did not use long‐term safety data from cross‐over or within‐participant trials due to the high likelihood of contamination.

For safety data, we reported adverse events at the end of treatment and the end of follow‐up (where specified).

Primary outcomes

Two primary outcomes were included — effectiveness (clinician‐reported signs of eczema) and safety — to reflect the overall aim of this review.

Changes in clinician‐reported signs of eczema (effectiveness). We extracted data based on the following priority order of instruments.Eczema Area and Severity Index (EASI) – this is the HOME‐recommended core outcome measurement instrument for clinician‐reported signs of eczema (Hanifin 2001; Schmitt 2014).Objective SCORing Atopic Dermatitis (ObjSCORAD) – measures similar aspects of the disease to EASI (Kunz 1997; Oranje 2007)SCORing Atopic Dermatitis (SCORAD) – objective SCORAD plus itch and sleep loss (Kunz 1997; Oranje 2007)Six Area, Six Sign Atopic Dermatitis (SASSAD) severity score (Berth‐Jones 1996)Three Item Severity score (TIS) (Oranje 2007; Willemsen 2009; Wolkerstorfer 1999)Investigator Global Assessment (IGA) – no validated instrument and little consistency between trials but commonly included (Futamura 2016)Any other instrumentsNumber of relevant local adverse events (safety). This included skin thinning, striae, telangiectasia, aging/wrinkling, changes in skin colour, sensitisation, skin bleaching, worsening or induction of acne, skin infections, folliculitis, perioral/periocular dermatitis, and application site reactions such as burning sensation/stinging. We only included local site reactions that resemble symptoms of eczema (e.g. itching), where they were indicated to be adverse events by the authors of the included trials. In our analyses, our primary focus was on the number of participants with at least one adverse event where this was possible (see: Measures of treatment effect).

Secondary outcomes

Patient‐reported symptoms of eczema (effectiveness). We extracted data based on the following priority order of instruments.Patient‐Oriented Eczema Measure (POEM) – recommended core instrument by HOME for the patient‐reported symptoms of eczema (Charman 2004 Spuls 2017).Patient‐Oriented SCORAD (PO‐SCORAD) (Vourc'h‐Jourdain 2009)Sleep and itch scales, as measured by Visual Analogue Scales (VAS) or Numerical Rating Scales (NRS)Self‐Administered EASI (SA‐EASI) (Housman 2002)Patient Global Assessment (PGA) – no validated instrument and little consistency between trialsAny other instrumentsNumber of relevant systemic adverse events (safety). This included bone problems, impact on growth and development, effects on endocrine system, eye problems, and cancer. In our analyses, our primary focus was on the number of participants with at least one adverse event where this was possible (see: Measures of treatment effect).

Search methods for identification of studies

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

Electronic searches

The Cochrane Skin Information Specialist searched the following databases up to 28 January 2021 using strategies based on the draft strategy for MEDLINE in our published protocol (Chalmers 2019).

the Cochrane Skin Specialised Register (Cochrane Skin Specialised Register 2021) using the search strategy in Appendix 1;the Cochrane Central Register of Controlled Trials (CENTRAL); 2021, Issue 1, in the Cochrane Library using the strategy in Appendix 2;MEDLINE via Ovid (from 1946 onwards) using the strategy in Appendix 3; andEmbase via Ovid (from 1974 onwards) using the strategy in Appendix 4.

We accessed the GREAT database (Global Resource for EczemA Trials (Centre of Evidence Based Dermatology) at www.greatdatabase.org.uk on 19 July 2018 (browsed to the Topical corticosteroids section and exported all relevant records). GREAT has not been updated since 2017 so we did not undertake any further searches of this database.

Trials registers

We (EA) searched the following trials registers using the search terms 'eczema' and 'atopic dermatitis'.

ClinicalTrials.gov (www.clinicaltrials.gov) searched to 28 January 2021;The World Health Organization International Clinical Trials Registry Platform (ICTRP; trialsearch.who.int/) searched to 21 November 2018.  It was unavailable in January 2021 so we were unable to update the search.

We searched the following three registries to 21 November 2018.  We did not identify any unique records, therefore we did not search them when we updated our searches in January 2021.

The ISRCTN register (www.isrctn.com);the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au); andthe EU Clinical Trials Register (www.clinicaltrialsregister.eu).

Searching other resources

Searching reference lists

We checked the bibliographies of included trials and any relevant systematic reviews identified for further references to relevant trials.

Correspondence with trial authors

We contacted trial authors for clarification and further data if trial reports were unclear (Table 10).

Correspondence with pharmaceutical companies

We emailed all of the pharmaceutical companies listed as manufacturers of topical corticosteroids in the  British National Formulary 2020. Correspondence with pharmaceutical companies is listed in Table 11.

Correspondence with regulatory agencies

We contacted the Medicines and Healthcare products Regulatory Agency (MHRA) to request Public Assessment Reports prior to 2005; none were available. We checked the MHRA website for Public Assessment Reports published for topical corticosteroids after 2005; none were identified.

Adverse effects

We did not perform a separate search for adverse effects of the target interventions. We considered adverse effects described in included trials only.

Data collection and analysis

We used Covidence systematic review software to screen and manage the references, and a Microsoft Access database (designed by SJL; piloted by SJL, JH and EA) to record the data extracted from the included trials.

Selection of studies

Two review authors (of EA, JH and SJL) independently screened the titles and abstracts of each record identified in the searches. If a trial met our inclusion criteria, we analysed the full text to confirm its inclusion. A third review author (JRC or HCW) resolved any disagreement. We recorded reasons for exclusions in Characteristics of excluded studies. We presented the process of trial selection in a PRISMA flow diagram (Page 2021).

Data extraction and management

Two review authors (of EA, JH, LJH and SJL) independently extracted data from each included trial using a data extraction form. We piloted and modified the form, as necessary. We extracted the following data.

Trial population (e.g. inclusion criteria, setting/country, severity of eczema, age, gender, ethnicity)Trial methods (e.g. trial design, blinding methods, funding source)Interventions and comparators (e.g. treatment name, frequency of use)Primary and secondary outcomes (including time points – both during treatment and during follow‐up)

We entered trial characteristics into a Characteristics of included studies table and we analysed or narratively described extracted outcome data. We resolved any disagreements during the data extraction phase through discussion with a third review author (JRC or HCW).

We included multiple reports of a trial but chose a primary reference and listed the others as secondary references. In some cases, we included more than one trial from one publication. It should also be noted that, for trials with more than two arms, the arms appear as more than one instance of the same trial, enabling all the relevant data to be included in the review, taking care to avoid double counting.

We translated non‐English language papers using Google Translate or asked a native speaker. If there were any serious ambiguities identified using Google Translate we consulted a native speaker.

We also extracted trial characteristics for ongoing trials to produce a Characteristics of ongoing studies table. We described trials awaiting classification in as much detail as possible in the Characteristics of studies awaiting classification where there was not enough information available for us to include or exclude the trial in the review.

Assessment of risk of bias in included studies

Two authors (of EA, JH, LJH and SJL) independently assessed the risk of bias of each included trial using the Cochrane risk of bias tool (RoB 1; Higgins 2011). We assessed the following domains.

Selection bias (random sequence generation and allocation concealment)Performance bias (blinding of participants and trial personnel)Detection bias (blinding of outcome assessment)Attrition bias (completeness of data, missing data and losses to follow‐up, intention‐to‐treat principle)Reporting bias (selective reporting of outcomes, assessed via comparing with the trial’s protocol or clinical trial register entry)Other bias (including design‐specific risks of bias, baseline imbalance, contamination, fraud, selective reporting of subgroups)

We assessed each domain as low, unclear or high risk of bias. We resolved disagreements by discussion with a third review author (JRC). We presented a risk of bias graph (Figure 2) and risk of bias summary figure (Figure 3) in the review.

Measures of treatment effect

Many of our pooled analyses required a generic inverse variance (GIV) approach to enable parallel‐group and within‐participant trials to be pooled alongside one another. Therefore, we reported dichotomous data as odds ratios (OR) with associated 95% confidence intervals (CI). One exception was the weekend therapy comparison where we reported relapse risk as a risk ratio to extend the previous meta‐analysis by Schmitt 2011.

We reported continuous data as mean differences (MD) with associated 95% confidence intervals (CIs), where trials used the same scale to measure an outcome. Where appropriate, we used a standardised mean difference (SMD) and associated 95% CI when trials used different instruments to measure effectiveness outcomes (i.e. clinician‐reported signs and patient‐reported symptoms).

Where trials reported time‐to‐relapse data based on a measure of effectiveness (e.g. EASI), we extracted hazard ratios (HR) from the trial reports. We  pooled log‐rank and Cox model estimates using the GIV approach according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021a).

For adverse event data, we reported the number of participants who experienced an event within the intervention and the control group, unless specified otherwise. We could not pool these data due to the low number of events. When judging whether a participant was deemed to have cortisol levels out of range, in the first instance we accepted what the trial report stated as the number of participants outside of the normal range whether they reported their reference range or not. If the trial did not tell us how many participants were deemed to be outside the normal range but did tell us cortisol test results, we used guidelines (referenced) to classify the participants. A clinical member of the author team reviewed these decisions.

We include contact with trial authors, where published data were ambiguous, in Table 10.

Unit of analysis issues

The unit of analysis was primarily the individual participant. To enable within‐participant trials to be pooled alongside parallel‐group trials we  performed variance corrections using the Becker‐Balagtas method (Elbourne 2002). We assumed an intra‐class correlation coefficient (ICC) of 0.5 in our calculations, but also undertook sensitivity analyses using 0.25 and 0.75 to explore this choice (see Table 12). We used a continuity correction of 0.5 in the case of zero events (Sweeting 2004).

For within‐participant trials where body parts received different interventions, we did not extract data on outcomes that affect the whole body (e.g. systemic adverse events), as it was not possible to determine which treatment caused the event.

For trials that included multiple intervention groups, we analysed each intervention group versus a comparator in a separate analysis, or combined groups to create a single pairwise comparison, if clinically appropriate (Higgins 2021a).

In order to generate clear summary statistics, where trials reported several signs of skin thinning, for example, telangiectasia, transparency, and thinning itself, we only collated the numbers of participants stated to have skin thinning. This was to avoid double counting.

For cross‐over trials, we planned to only use data from the first part of the trial or to narratively describe the results. We had also planned to only meta‐analyse cluster‐RCTs with parallel RCTs if the data reported in the trial publication had been correctly analysed, taking into account the number of clusters, or if appropriate, estimating the intracluster correlation coefficient (Higgins 2021b). However, we did not meta‐analyse any cluster or cross‐over trials in the review.

Dealing with missing data

Where possible we conducted an intention‐to‐treat analysis, including all randomised participants where data were provided. If data were missing, we contacted trial authors and produced a table in the review detailing such contact (e.g. dates, information requested, whether they replied; Table 10). If it was not possible to obtain clarification, we discussed whether to assume the number randomised or an otherwise similarly sensible estimate. We have indicated clearly where we have done this, or we have reported the ambiguous data narratively.

We conducted sensitivity analyses, removing trials at high risk of attrition bias (see Table 13) and we also considered attrition bias when undertaking our quality assessments (Schünemann 2013).

For dichotomous data, we performed any calculations necessary to pool data divided by a similar threshold, for example, we combined results from multiple subclasses, or calculated exact numbers from reported percentages (rounding sensibly).

For continuous data, we attempted to calculate any missing statistics (e.g. standard deviations) using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2021). Where it was necessary to assume an ICC of 0.5 in our calculations we  undertook sensitivity analyses using 0.25 and 0.75 to explore this choice (see: Table 14).

For time to event data, we performed calculations of missing HR from the statistics that were available according to Parmar 1998.

Assessment of heterogeneity

When pooling trials in a meta‐analysis, we considered any methodological and clinical differences between trials, and only included trials in the same meta‐analysis where it was considered appropriate. We assessed heterogeneity through forest plot inspection and the I² statistic (Higgins 2003), using the thresholds defined in the Cochrane Handbook for Systematic Reviews of Interventions: 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; and 75% to 100% represents considerable heterogeneity (Deeks 2021). If we identified substantial or considerable statistical heterogeneity, we attempted to determine reasons for this by examining the trial characteristics and performing subgroup and sensitivity analyses where appropriate.

Assessment of reporting biases

If we included 10 or more trials in a meta‐analysis, we produced a funnel plot to explore publication bias (Sterne 2011). We described suspected reporting biases narratively and their potential effects on the overall results and conclusions.

Data synthesis

We narratively synthesised outcome data and conducted meta‐analysis (where appropriate) in Review Manager 5.4, using the random‐effects model (Review Manager 2020). We used the GIV model for meta‐analyses, which included within‐participant trials and displayed the effect sizes as ORs. We presented effect estimates, with 95% CIs and associated I² statistic and P values, for all pooled synthesis. For dichotomous outcomes, where a statistical evidence of an effect is reported we calculated an associated number needed to treat for an additional beneficial outcome (with associated 95% CIs).

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses.

Children versus adultsAnatomical site, for example, topical corticosteroid applied to sensitive sites (face/genitals) versus other body sitesBaseline severity of eczema (mild disease versus moderate and severe, as specified in the trial report)

If there was substantial statistical heterogeneity (via forest plot inspection and using the I² statistic), we investigated additional clinical and methodological differences. Clinical differences could have included filaggrin (FLG) mutation status, age subgroups of children (0 to 4, 5 to 11, and 11+ years), chronic versus acute disease, and body surface area affected.

Sensitivity analysis

We performed a sensitivity analysis removing trials at high risk of bias from the meta‐analysis (Table 13). We also performed sensitivity analyses where necessary, where we made assumptions or imputed data.

Summary of findings and assessment of the certainty of the evidence

We created summary of findings tables for our main comparisons. We selected the following four most relevant and important comparisons, from both clinician and patient perspectives, to be included in the summary of findings tables.

Stronger potency versus weaker potency for treatment of eczema flare‐upsTwice daily versus once daily application for treatment of eczema flare‐upsLonger‐ versus shorter‐term application for induction of remissionTwice weekly application to prevent relapse (weekend therapy) versus no application

We included both primary outcomes and secondary outcomes in each summary of findings table. We used the GRADE approach to assess the certainty of evidence for each primary and secondary outcome for our main comparisons. GRADE includes the assessment of five trial limitations (risk of bias); inconsistency of results; indirectness of evidence; imprecision; and publication bias (Schünemann 2013). Each outcome can be downgraded by one or two levels for each domain, and we classed the overall certainty as high, moderate, low or very low. We used GRADEpro GDT to create our summary of findings tables and undertake our GRADE assessments.

Results

Description of studies

See: Characteristics of included studies, Characteristics of studies awaiting classification, Characteristics of ongoing studies, and Characteristics of excluded studies.

Results of the search

Our searches of the electronic databases and trials registers (see Electronic searches) retrieved 5355 records. The Cochrane Skin Information Specialist removed duplicates from this group, using EndNote's duplicate identification strategy. We found five additional records through handsearching. We removed a further 69 duplicate records and screened 5291 titles and abstracts for eligibility, and excluded 4619. We sought full texts associated with the remaining 672 records, over 150 of which required translation of key methods text into English. We found 183 to be clearly irrelevant, for example, because they were not RCTs, or were not conducted in people with eczema. We excluded a further 303 trials reported in 309 references, with reasons given in the Characteristics of excluded studies (mostly ineligible trial design); 23 are awaiting classification primarily because we could not obtain full texts (see: Characteristics of studies awaiting classification); and a further six trials reported in 10 references are ongoing (see: Characteristics of ongoing studies).

We included 104 trials reported in 147 references. Seventeen required translation into English from a number of other languages (see: Acknowledgements for where this was done outside the review team): Czech (Fadrhoncova 1982); Dutch (Sillevis 2000); French (Craps 1973; Lebrun‐Vignes 2000); German (Busch‐Heidger 1993; Harder 1983; Mahrle 1989; Meffert 1999; Nolting 1991; Ruiz 1976; Ulrich 1991); Italian (Amerio 1998; Giannetti 1981; Innocenti 1977); Korean (Ryu 1997); Portuguese (Van Del Rey 1983); and Spanish (Sanabria‐Silva 1991). For a further description of our screening process, see the trial flow diagram (Figure 4).

Sample size

We included 104 trials, with a total of 8443 participants (range 3 to 409;  Characteristics of included studies). Over half were parallel‐group trials (63/104); 39 were within‐participant trials; two were cross‐over trials (Dolle 2015; Kohn 2016).

Setting

Most trials were conducted in high‐income countries (81/104): Europe (52); USA (22); Japan (2); South Korea (2); Canada (1); Hong Kong (1); Singapore (1). An additional two were conducted across multiple centres in both high‐ and upper‐middle‐income countries (Kirkup 2003a; Kirkup 2003b). Five were conducted in the following upper‐middle‐income Brazil (2); China (1); Malaysia (1); and Mexico (1). Three were conducted in the following lower‐middle‐income India (2); and Bangladesh (1). It was not possible to report or infer where the remaining 13 trials were conducted. We classified countries according to the current classification by World Bank.

Approximately half of the trials (51/104) were conducted in outpatient or other hospital settings, with an additional three trials working across both community and hospital settings (Kohn 2016; Rubio‐Gomis 2018; Thomas 2002). Three trials were conducted in private dermatology clinics (Cullen 1971; Mali 1976; Noren 1989). The nature of the trial setting was unspecified in the remaining 47 trials, but is most likely be outpatient or other hospital settings.

Participants

Forty‐three trials included children only, 16 included adults only, and 17 included both adults and children. Twenty‐eight trials did not specify the age of participants. Sex was specified in 82/104 trials, with all including male and female participants, and with one trial noting that sex was not reported for one participant (Lasthein Andersen 1988).

Half the trials included participants with moderate or severe eczema (51/104) and 16/104 with mild to moderate eczema. Three trials included participants with mild to severe eczema. Thirty‐four trials did not report participants’ baseline severity of eczema.

Interventions and comparisons

See: Figure 1; overview of strategies included in the review.

Which topical corticosteroid to use?

Moderate‐ versus mild‐potency topical corticosteroid* (12 trials in 1184 participants)Potent versus mild‐potency topical corticosteroid* (22 trials in 1010 participants)Potent versus moderate‐potency topical corticosteroid* (25 trials in 1515 participants)Very potent versus potent topical corticosteroid* (6 trials in 730 participants)Topical corticosteroid cream versus topical corticosteroid ointment (7 trials in 677 participants)Different concentrations of the same topical corticosteroid (2 trials in 401 participants)Second‐generation topical corticosteroid versus older topical corticosteroid (15 trials in 1248 participants)Branded topical corticosteroid versus generic topical corticosteroid (no trials)

How often to apply topical corticosteroid?

Twice or more versus once daily application of topical corticosteroid* (25 trials in 2862 participants)Daily application versus less frequent application (4 trials in 327 participants)Longer‐ versus shorter‐term duration of use for induction of remission* (no trials)Topical corticosteroid alternating with topical calcineurin inhibitor versus topical corticosteroid alone (1 trial in 30 participants)Weekend therapy (proactive topical corticosteroid) versus no proactive topical corticosteroid* (9 trials in 1344 participants)

How to use the topical corticosteroid?

Timing of application of topical corticosteroid (2 trials in 158 participants)Wet wrap versus no wet wrap (6 trials in 221 participants)Topical corticosteroid applied to wet versus dry skin (1 trial in 45 participants)Topical corticosteroid applied before emollient versus topical corticosteroid applied after emollient (1 trial in 46 participants)Time between application of emollient and steroid (no trials)

*Key comparisons for which summary of findings tables are presented.

Several included trials tested a combination of the above, reflecting how topical corticosteroids might be used in clinical practice, therefore, are found in more than one results section. For instance, Rafanelli 1993 compares a newer, second‐generation potent topical corticosteroid (mometasone furoate) applied once daily with a moderate‐potency, older topical corticosteroid (clobetasone butyrate) used twice daily. As a result, Rafanelli 1993 is included in three separate meta‐analyses; 1. potency versus moderate topical corticosteroid; 2. second‐generation versus older topical corticosteroid; and 3. frequency of application, and the comparison of interest changes for each.

Trials that compared treatment strategies designed to treat eczema flares were generally short‐term (range 1 to 6 weeks) and rarely conducted any follow‐up. Trials included in the comparison of weekend (proactive) therapy with topical corticosteroid versus no topical corticosteroid, where the intervention aimed to prolong time to new flare (i.e. prevent relapse), were longer in duration. These trials involved a two‐ to four‐week stabilisation phase where both groups received topical corticosteroid, followed by a 16‐ to 20‐week maintenance phase, with the exceptions of Fukuie 2012 and Fukuie 2016, which observed participants at 6 and 12 months, respectively.

Outcomes

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

The number of included trials from which clinician‐reported data have been used in this review is detailed below against the protocol‐specified priority order of instruments.

Eczema Area and Severity Index (EASI): five trials, one of which had factored patient assessment of itch into a composite scoreObjective SCORing Atopic Dermatitis (ObjSCORAD): three trials, one of which used objective local SCORADSCORing Atopic Dermatitis (SCORAD): three trialsSix Area, Six Sign Atopic Dermatitis (SASSAD) severity three trialsThree Item Severity score (TIS): two trialsInvestigator Global Assessment (IGA): 62 trials, three of which had factored patient responses into the judgementsAny other seven trials of weekend therapy versus no topical corticosteroid reported time to  relapse and number of participants experiencing a relapse; unnamed scales were used from 18 trials.No useable two trials

One of these trials (Berth‐Jones 2003), included TIS data from the end of the acute phase in short‐term outcomes for topical corticosteroid cream versus topical corticoid steroid ointment, different concentrations of the same topical corticoid steroid, and twice or more versus once daily topical corticoid steroid; relapse data from the end of the maintenance phase are included in weekend (proactive) therapy versus no topical corticoid steroid.*

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

The number of included trials from which patient‐reported data have been used in this review is detailed below against the protocol‐specified priority order of instruments.

Patient‐Oriented Eczema Measure (POEM): no trialsPatient‐Oriented SCORAD (PO‐SCORAD): no trialsSleep and itch eight trials reported itch; eight reported both itch and sleep separately; one trial reported itch and sleep in a composite score; and another reported EASI and itch as a composite scoreSelf‐Administered EASI (SA‐EASI): no trialsPatient Global Assessment (PGA): 15 trials, three of which were IGA factoring patient responses into the judgements.Any other two trials reported unnamed scales, one of which had an itch component.No useable 69 trials

Safety: number of relevant local adverse events (primary outcome)

The number of included trials that looked for relevant local adverse events incorporated into this review is detailed below, against the main groupings.

Skin 33 trialsLocal site 39 trials, one of which did not report the data separately for the comparison of interest to this review.Skin 23 trials, one of which did not report the data separately for the comparison of interest to this review.Other relevant local adverse four trials

Safety: number of relevant systemic adverse events (secondary outcome)

The number of included trials that looked for relevant systemic adverse events incorporated into this review is detailed

Abnormal 17 trials, only one of which looked for clinical signs of adrenal suppression.Other relevant systemic adverse 13 trials, one of which did not report the data separately for the comparison of interest to this review. Rarely was information given to the nature of the systemic adverse events looked for.

Funding sources

Fourteen trials were funded by pharmaceutical companies (Berth‐Jones 2003; Bleehen 1995; Foelster‐Holst 2006; Glazenburg 2009; Guttman‐Yassky 2017; Hanifin 2002; Kirkup 2003a; Kirkup 2003b; Lebwohl 1999; Liu 2018; Schlessinger 2006; Van Der Meer 1999; Vernon 1991; Yawalkar 1991). Two trials were explicitly conducted in industry settings (EUCTR2009‐012028‐98‐DE; Lucky 1997). Another trial not declaring funding source or conflicts of interest (Tharp 1996) is likely to be an industry‐based trial as two of the four references in the bibliography of the article are to industry documentation and data on file. Three trials were funded by healthcare providers; two by the NHS Research and Development Fund (Hindley 2006; Thomas 2002), and another by Seton Healthcare (Cadmus 2019). Four trials received charitable or other public funding (Bryden 2009; Fukuie 2016; Kohn 2016; Rubio‐Gomis 2018).

Eleven trials received treatments, other trial materials, or more general trial support from industrial partners (Cahn 1961; Cullen 1971; Handa 1985; Haribhakti 1982; Hoybye 1991; Meenan 1963; Pei 2001; Portnoy 1969; Sikder 2005; Stewart 1973; Wortzel 1975). One trial reported being sponsored by a pharmaceutical company (Koopmans 1995). Two further trials acknowledged the support of industrial partners but did not provide details regarding the nature of the support (Reidhav 1996; Wilson 2009).

Of the remainder, 22 trials did not report funding source, but declared interest in, or affiliation to, pharmaceutical companies. Neither funding source nor declarations of interest were reported by 44 trials.

Excluded studies

We excluded 302 trials reported in 309 references with reasons given in the Characteristics of excluded studies.

Risk of bias in included studies

We assessed each trial with regards to the seven criteria defined within the Cochrane risk of bias tool (RoB 1). For a summary of all the judgements  Figure 2 and Figure 3. We judged only one trial, which assessed weekend (proactive) topical corticosteroid treatment versus no proactive treatment, to be at low risk of bias throughout all domains (Rubio‐Gomis 2018). Of the remaining 103 trials, we assessed 55 as having at least one domain at high risk of bias. We did not judge any trials to be at high risk of bias in all domains. We assessed the remaining 48 trials as unclear in at least one domain.

Allocation

Although we selected only RCTs for this review, we judged only 16 of the 104 (15%) to be low risk of bias in the 'random sequence generation' domain and nine of the 104 (9%) to be low risk of bias in the 'allocation concealment' domain. Conversely, we judged seven of the 104 (7%) trials to be at high risk of bias for 'random sequence generation' and one of the 104 (1%) at high risk of bias for the 'allocation concealment' domain. Therefore, we judged most trials to be unclear in these domains. This was usually because they did not give a description of the method of randomisation and allocation at all or did not describe their methods in enough detail to allow assessment. Most of the trials that we assessed as being at low risk in the 'random sequence generation' domain used either random number tables or computer‐generated methods of allocation. The trials that we judged at low risk of bias in the 'allocation concealment domain' explicitly stated that the investigator did not know the treatment allocation or mentioned that allocation was done by a third party.

Blinding

Performance bias

We assessed 14 out of the 104 trials as being adequately blinded in this domain. In contrast, we judged 28 out of the 104 trials to be at high risk of bias within this domain. This meant that the we judged the majority of trials (62) to be unclear with regards to assessment of this domain. In some comparisons, due to the nature of the strategies, it would have been very difficult to blind the participants and the personnel, for example we judged all six of the trials that assessed the use of wet wrap therapy at risk of bias in this area and it would have been difficult to avoid this problem. This was also the case in other trials that assessed other strategies, for example in the trial that assessed ointment versus cream under wet wraps (1 trial), the trial that evaluated the application on dry skin versus wet skin (1 trial), and the trial that tested whether to apply topical corticosteroid first or emollient first (1 trial). An additional problem was that many trials did not specifically mention who was blinded. For example, the trial may have stated “single‐blinded” or “double‐blinded” but there was no mention of who the blinded parties were, or the paper did not mention blinding at all. There was also a number of trials, 10 out of the 28 judged at high risk of bias in this domain, where participants were applying treatments at different frequencies per day. In some cases, a placebo was not used at the same time as the other group were applying topical corticosteroid, though this may have been a conscious decision by the trial authors, due to the risk of the placebo acting as an active agent.

Detection bias

We assessed 27 out 104 trials as adequately blinded in this domain, seven at high risk of bias, and 70 trials where the information was unclear and so we could not make a judgement. Again, there were problems with the trials stating “single blinded” or “double‐blinded” and then not stating which of the parties were blinded and problems with trials not providing any details as to whether any efforts were made to blind assessors.

Incomplete outcome data

We assessed 42 out of 104 trials as being at low risk of bias in this domain, 19 at high risk of bias and 43 trials as unclear. Trials were likely to have been marked as at high risk of bias in this domain because a large proportion of the participants were unaccounted for in the results of the trial, in some cases because participants were dropped from the trial when they achieved clearance of their eczema symptoms.

Selective reporting

Out of the 104 trials included in the review, we judged 84 at unclear risk of reporting bias. We judged only three trials to be at low risk and 17 at high risk. This was usually because, if there was not a trial protocol available for the trial, we were not able to compare the a priori outcomes, and so again we judged this domain as unclear. As around 80% of the trials included in this review were from before 2005, when registration was required for publication by a consensus statement from the International Committee of Medical Journal Editors (De Angelis 2004), this is probably the reason for this issue.

Other potential sources of bias

We judged most of the trials at low risk of bias in this domain (86 trials). For the eight trials that we judged at high risk of bias, the reasons were differences in co‐interventions in the two groups (Foelster‐Holst 2006), problems with selection of an unrepresentative population (Giannetti 1981), violations in the trial protocol (Hanifin 2002), trial potentially stopped prematurely (Munro 1967), mismatches in baseline severity (Pei 2001), and lack of information about methodologies (Sefton 1984a; Sefton 1984b; Sefton 1984c). We judged the 10 remaining trials to be unclear.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7

See Table 1: Moderate‐ versus mild‐potency topical corticosteroid; Table 2: Potent versus mild‐potency topical corticosteroid; Table 3: Potent versus moderate‐potency topical corticosteroid; Table 4: Very potent versus potent topical corticosteroid; Table 5: Twice or more versus once daily topical corticosteroid; Table 6: Duration of use for induction of remission; and Table 7: Weekend therapy versus no topical corticosteroid.

We reported all relevant outcomes from the included trials for 18 pairwise comparisons. We considered seven of these the main comparisons in our review because of their relevance to clinical practice, and we rated the quality of evidence for these outcomes using GRADE.

We have performed subgroup analyses throughout, where there were sufficient data, with respect to age and baseline severity of eczema. As there were consistently insufficient data with which to compare effectiveness at different anatomical sites it was not possible to conduct subgroup analyses for any of the comparisons in this review.

Where possible, we did sensitivity analyses removing trials at high risk of bias. The results were generally consistent or based on insufficient trials (see: Table 13), and points of particular interest are highlighted under the relevant comparison. In addition, we examined the effects of Becker‐Balagtas correction of the variance from within‐participant trials, and imputation of missing standard deviations for a range of intraclass correlation coefficients (0.25, 0.5 and 0.75; Table 12 and Table 14).

Potency comparisons

Strategies in this review regarding potency were focused on clinically relevant comparisons that reflected the 'stepping‐up' strategies for treating eczema, including moderate versus mild, potent versus mild, potent versus moderate, and very potent versus potent topical corticosteroid.

Moderate‐ versus mild‐potency topical corticosteroid

See: Table 1.

This comparison comprises 12 trials; six parallel‐group (Bagatell 1983; Jorizzo 1995; Lucky 1997; Mobacken 1986; Queille 1984; Rossi 2002) and six within‐participant (Haribhakti 1982; Kuokkanen 1987; Meenan 1963; Munro 1975; Portnoy 1969; Roth 1978a). In all trials only the potency of topical corticosteroid varied between groups, none compared multiple strategies.

Data were available for all outcomes relevant to this review.

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

Eleven trials included in this comparison measured clinician‐reported signs of eczema. Taken together, we judged the certainty of evidence was judged to be moderate.

####### Pooled moderate‐ versus mild‐potency topical corticosteroid

**Investigator global assessment (IGA)**We pooled results from four trials for IGA as a short‐term outcome (range 1 to 5 weeks; Bagatell 1983; Jorizzo 1995; Mobacken 1986; Roth 1978a), that included 420 participants; 391 from the parallel‐group trials and 29 from the within‐participant trial (Roth 1978a). The trials used a 5‐, or 6‐point scale and we pooled data from categories corresponding to ‘cleared or marked improvement’. In the parallel‐group trials, 86 of 195 participants who used moderate topical corticosteroid achieved cleared or marked improvement in the short‐term compared to 60 of 196 participants who used mild topical corticosteroid. In the within‐participant trial, 24 of 29 sides achieved cleared or marked improvement when treated with moderate topical corticosteroid compared to 17 of 29 sides treated with mild topical corticosteroid (OR 2.07, 95% CI 1.41 to 3.04; P = 0.0002; I² = 0%; 4 trials, 449 participants or sides treated; Analysis 1.1), indicating that moderate‐potency topical corticosteroid is more effective than mild‐potency topical corticosteroid. It is expected that one additional person will achieve success for every six participants receiving moderate topical corticosteroid rather than mild topical corticosteroid (95% CI 4 to 12). We were unable to perform subgroup analyses of trials in adults compared to children owing to the lack of trials in adults only, so we restricted the previous analysis to children only. Two parallel‐group trials (Jorizzo 1995; Mobacken 1986), reported IGA as a short‐term outcome (day 7 to 10), with 169 participants. The OR for achieving cleared or marked improvement was 2.11 (95% CI 1.08 to 4.13; P = 0.03; I² = 0%; 2 trials, 169 participants; Analysis 1.2), in favour of moderate topical corticosteroid. The three trials that reported baseline severity of eczema were all different severities, therefore subgroup analyses were not appropriate with respect to severity.We found similar results at end of treatment both overall (range 3 to 5 weeks; Bagatell 1983; Jorizzo 1995; Mobacken 1986; Roth 1978a; OR 2.74. 95% CI 1.47 to 5.11; P = 0.002; I² = 53%; 4 trials, 427 participants or sides treated; Analysis 1.3); and in children only (range 3 to 5 weeks; OR 3.90, 95% CI 1.84 to 8.25; P = 0.0004; I² = 6%; 2 trials, 169 participants; Jorizzo 1995; Mobacken 1986; Analysis 1.4). Investigator assessment of clinical signsWe pooled results from two trials (Haribhakti 1982; Queille 1984), for investigator assessment of clinical signs as a short‐term outcome in children with moderate to severe eczema. There were 30 participants; nine from the parallel‐group trial (Queille 1984), and 21 from the within‐participant trial (Haribhakti 1982). The standardised mean difference (SMD) at day 6 to 7 was a decrease of 0.15 (95% CI −0.27 to 0.56; P = 0.49; I² = 0%; 2 trials, 51 participants or sides treated; Analysis 1.5), suggesting no difference between groups in contrast to the pooled IGA data. We found similar results for end of treatment (range 1 to 3 weeks; SMD 0.43, 95% CI 0.00 to 0.86; P = 0.05; I² = 0%; 2 trials, 51 participants or sides treated; Analysis 1.6). Subgroup analysis was not possible because all trials included in SMD Analysis 1.5 and Analysis 1.6 included children with moderate to severe eczema only.Number of participants with a greater investigator global assessment (IGA)/patient global assessment (PGA) compared to the other groupWe pooled data from three within‐participant trials (Meenan 1963; Munro 1975; Portnoy 1969), that included 472 participants, for IGA, in the form of the number of participants for which each topical corticosteroid was judged to be better than the other, as a short‐term outcome and at end of treatment. Two of the trials (Meenan 1963; Portnoy 1969; 64 participants), combined patient judgement with clinician judgement. Moderate topical corticosteroid was judged to be better in 180 participants; mild topical corticosteroid was judged to be better in 106 participants. The OR for the clinician judging one topical corticosteroid to be superior to the other was 3.14 (95% CI 1.39 to 7.13; P = 0.006; I² = 91%; 3 trials, 472 participants; Analysis 1.7). This suggests that moderate topical corticosteroid was more effective than mild‐potency topical corticosteroid in line with the pooled IGA analysis, although this result has a high degree of imprecision and statistical heterogeneity. The increasing concentration of moderate topical corticosteroid used in the moderate arms of Munro 1975 is reflected in how they increasingly favour moderate topical corticosteroid; Meenan 1963 appears as an outlier because none of the participants favoured the mild topical corticosteroid; an artefact of using the generic inverse variance approach to enable consistent pooling of within‐participant trials across this review. Removing the trials judged high risk of bias inflated the result and expanded the 95% confidence interval to include 1 (see: Table 13); OR = 37.51 (95% CI 0.34 to 4133.15).Only Meenan 1963 specified they investigated children only (Analysis 1.7), and none of the trials reported baseline severity, therefore no subgroup analyses were possible.Data not included in the meta‐analysesWe could not include two trials in the meta‐analyses because the numerical data were incomplete. We have summarised these in Analysis 1.8. They did not show any difference between moderate and mild‐potency topical corticosteroid.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

Five trials reported this outcome in 356 participants (range 1 to 5 weeks). Taken together, we judged the certainty of evidence to be low.

We combined parent or participant judgements with investigator assessments in two within‐participant trials (Meenan 1963 in children with unspecified disease severity; Portnoy 1969 in participants with unspecified age and disease severity; 64 participants), and pooled the data  (Analysis 1.7). Results favoured moderate over mild‐potency topical corticosteroid. Three additional parallel‐group trials in 292 participants (263 from parallel‐group trials and 29 from a within‐participant trial), summarised in Analysis 1.9, were also in favour of moderate topical corticosteroid (Jorizzo 1995; Rossi 2002; Roth 1978a).

Safety: number of relevant local adverse events (primary outcome)

Five trials reported on local adverse events (Bagatell 1983; Haribhakti 1982; Jorizzo 1995; Kuokkanen 1987; Roth 1978a), that included 446 participants; 362 from the parallel‐group trials and 84 from the within‐participant trials (range 2 to 5 weeks). Taken together, we judged the certainty of evidence to be low.

####### Skin thinning and related signs

Four trials that compared moderate and mild topical corticosteroid of two to five weeks' duration assessed skin thinning and related signs; no cases were reported (Bagatell 1983; Haribhakti 1982; Jorizzo 1995; Kuokkanen 1987; 417 participants). No cases were reported in a subgroup of 36 participants treated for up to 25 weeks in Jorizzo 1995.

####### Local site reactions

Four trials that compared moderate and mild topical corticosteroid of two to five weeks' duration reported the number of participants who experienced local site reactions (Bagatell 1983; Jorizzo 1995; Kuokkanen 1987; Roth 1978a; Analysis 1.10). Some trials described adverse events as "brief" and "slight". The trial with the largest number of participants that reported local site reactions was Bagatell 1983 (4/127 with moderate topical corticosteroid and 3/122 with mild topical corticosteroid).

####### Skin infections

A three‐week trial that compared moderate (127 participants) and mild (122 participants) topical corticosteroid found no cases of folliculitis (Bagatell 1983).

Other adverse events are described under ‘Unspecified adverse events (safety)’.

Safety: number of relevant systemic adverse events (secondary outcome)

Three parallel‐group trials assessed systemic adverse events in 282 participants (range 1 to 4 weeks; Bagatell 1983; Lucky 1997; Queille 1984). Taken together, we judged the certainty of evidence to be very low.

Two trials reported the number of participants with abnormal cortisol levels. Lucky 1997 included children with unspecified eczema severity. Morning serum cortisol samples (obtained before 9 am) were taken at baseline and days 14 and 28, and serum cortisol values 30 and 60 minutes after adrenocorticotropic hormone (ACTH) stimulation were also taken at baseline and day 28. Queille 1984 included children with severe eczema. Plasma cortisol samples were taken at any visit up to day 6. For this review, we converted individual measurements to number of participants with levels outside a reference range (6 to 23 μg/dL or 170 to 635 nmol/L; Royal College, Canada). No cases were reported in either trial (Lucky 1997; Queille 1984; 33 participants).

Bagatell 1983 reported that no systemic adverse events occurred up to week 3 (249 participants).

Unspecified adverse events (safety)

Mobacken 1986 reported that no adverse events occurred in either group (up to day 25; 29 participants), and Rossi 2002 stated that both topical corticosteroids were “safe and well tolerated” up to 3 weeks (152 participants).

Potent versus mild‐potency topical corticosteroid

See: Table 2.

This comparison comprises 22 trials; 15 parallel‐group trials (Gentry 1973; Kaplan 1978; Kirkup 2003a; Lebrun‐Vignes 2000; Mali 1976; Marten 1980; Noren 1989; Prado de Oliveira 2002; Queille 1984; Ryu 1997; Sanabria‐Silva 1991; Savin 1976; Thomas 2002; Vernon 1991; Wortzel 1975), and seven within‐participant trials (Cahn 1961; Fadrhoncova 1982; Giannetti 1981; Handa 1985; Roth 1973; Veien 1984; Yasuda 1976). In 16 trials only the potency of topical corticosteroid varied between groups (single strategy), whilst the remaining six trials were a combination of multiple different strategies of topical corticosteroid use.

Of the six trials that tested multiple strategies, one trial compared a potent cream with a mild‐potency ointment (Kaplan 1978; age and severity unspecified). Two trials compared a second‐generation potent topical corticosteroid to an older mild‐potency topical corticosteroid (Kirkup 2003a; Prado de Oliveira 2002; both in children with moderate to severe eczema). A further two trials were similar, but the second‐generation potent topical corticosteroid was applied once daily compared to twice daily application of the older mild topical corticosteroid (Vernon 1991, in children with moderate to severe eczema; Ryu 1997, in adults and children over three years with mild‐ to moderate‐severity eczema). One trial compared a three day ‘pulse’ of potent topical corticosteroid with seven days of mild topical corticosteroid for management of flares in children with mild to moderate eczema (Thomas 2002).

Data were available for all outcomes relevant to this review.

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

All trials included in this comparison measured clinician‐reported signs of eczema. Taken together, we judged the certainty of evidence to be moderate.

####### Pooled potent versus mild‐potency topical corticosteroid

**Investigator global assessment (IGA)**We pooled IGA, as a short‐term outcome (range 1 to 4 weeks), from nine trials (Gentry 1973; Giannetti 1981; Handa 1985; Kirkup 2003a; Mali 1976; Ryu 1997; Savin 1976; Veien 1984; Wortzel 1975), that included 392 participants; 326 from the parallel‐group trials and 66 from the within‐participant trials. Most trials used a 4‐, 5‐, or 6‐point scale and we pooled data from categories corresponding to ‘cleared or marked improvement’ where possible. In the parallel‐group trials, 131 of 165 participants who used potent topical corticosteroid achieved cleared or marked improvement compared to 73 of 161 who used mild topical corticosteroid. In the within‐participant trials, 25 of 66 participants achieved cleared or marked improvement on the side treated with potent topical corticosteroid compared to 16 of 66 on the side treated with mild topical corticosteroid (OR 3.71, 95% CI 2.04 to 6.72; P < 0.00001; I² = 39%; 9 trials, 458 participants or sides treated; Analysis 2.1), indicating that potent topical corticosteroid is more effective than mild‐potency topical corticosteroid. This corresponds to a need to treat 3.2 people with potent topical corticosteroid to achieve an additional treatment success compared to mild topical corticosteroid (95% CI 2.4 to 5.7). We observed this effect in analyses of trials of a single strategy only, potent versus mild topical corticosteroid (Analysis 2.1.1; Analysis 2.1.2), as well as in multiple strategies including a second‐generation potent topical corticosteroid (Analysis 2.1.3), and a second‐generation potent topical corticosteroid applied once daily versus twice daily application of mild‐potency topical corticosteroid (Analysis 2.1.4). The short‐term time point was the end of treatment for over half of the trials; therefore, we did not carry out a separate end of treatment meta‐analysis. We were unable to perform subgroup analyses of adults and children owing to the lack of trials in adults only, so we restricted the previous short‐term IGA analyses to three trials in children (Giannetti 1981; Kirkup 2003a; Veien 1984). The OR for achieving cleared or marked improvement in the short term was 2.21 (95% CI 1.39 to 3.51; P = 0.0008; I² = 0%; 3 trials, 245 participants or sides treated; Analysis 2.2), in favour of potent topical corticosteroid, consistent with the overall finding. We then pooled IGA as a short‐term outcome from three trials that included participants with moderate to severe eczema (Kirkup 2003a; Savin 1976; Veien 1984). The OR for achieving cleared or marked improvement was 2.69 (95% CI 1.34 to 5.39; P = 0.005; I² = 35%; 3 trials, 232 participants or sides treated; Analysis 2.3.1), in favour of potent topical corticosteroid. Two trials included participants with mild to moderate eczema (Giannetti 1981; Ryu 1997). The OR for achieving cleared or marked improvement was 4.84 (95% CI 0.33 to 71.44; P = 0.25; I² = 80%; 2 trials, 63 participants or sides treated; Analysis 2.3.2). We observed no difference between the two groups when we pooled only trials in mild‐ to moderate‐severity eczema, however, the test for subgroup differences for Analysis 2.3 was not statistically significant, with a P value of 0.68, suggesting that potent topical corticosteroids are more effective than mild‐potency topical corticosteroids regardless of baseline severity of eczema.Investigator assessment of clinical signsWe pooled investigator assessment of clinical signs as a short‐term outcome (day 5 to 6) from two parallel‐group trials in 46 children with severe eczema (Lebrun‐Vignes 2000; Queille 1984). The SMD was a decrease of 0.63 (95% CI −0.95 to 2.21; P = 0.43; I² = 82%; 2 trials, 46 participants; Analysis 2.4) and therefore did not reflect the difference between potent and mild‐potency topical corticosteroid seen in the main pooled IGA analysis. The statistical heterogeneity is high; Queille 1984 favours potent topical corticosteroid while Lebrun‐Vignes 2000 shows no difference, but the number of participants is small, and the confidence intervals do overlap. The short‐term time point was the end of treatment for one of the trials, therefore we did not carry out a separate end of treatment meta‐analysis. Both trials included in SMD Analysis 2.4 included children with severe eczema only, therefore no further restricted analyses were required.Number of participants with a greater IGA compared to the other groupWe pooled IGA, in the form of the number of participants for whom each topical corticosteroid was judged to be better than the other, as a short‐term outcome (week 1), from three within‐participant trials in 67 participants (Cahn 1961; Roth 1973; Yasuda 1976). Roth 1973 included participants aged 18 months to 59 years with moderate to severe eczema; Cahn 1961 and Yasuda 1976 did not specify age and severity. The clinician‐reported potent topical corticosteroid to be superior to mild in 39 participants and mild to be superior in six (OR 11.70, 95% CI 5.67 to 24.15; P < 0.00001; I² = 0%; 3 trials, 67 participants; Analysis 2.5) in favour of potent topical corticosteroid. The short‐term time point was the end of treatment for two of the trials, therefore we did not carry out a separate end of treatment meta‐analysis. None of the trials included in Analysis 2.5 were in either adults or children only, and only one trial reported participants’ baseline severity (Roth 1973; moderate to severe eczema); therefore, no further subgroup or restricted analyses were possible.Data not included in the meta‐analysesWe could not include nine trials in the meta‐analyses, either because we could not pool the instrument used to measure clinician‐reported signs of eczema alongside those included (Thomas 2002), because the duration was too long relative to the short‐term outcomes pooled (Prado de Oliveira 2002), or because the numerical data were incomplete (Fadrhoncova 1982; Kaplan 1978; Kirkup 2003a; Marten 1980; Noren 1989; Sanabria‐Silva 1991; Vernon 1991), and are summarised in Analysis 2.6. Five trials suggest potent topical corticosteroid to be more effective than mild‐potency topical corticosteroid in line with the meta‐analyses favouring potent topical corticosteroid, but most are difficult to interpret with any certainty due to lack of information about the scale used or lack of dispersion data. The remaining four trials did not show any difference between the two potencies, including Thomas 2002, which compared mild topical corticosteroid used daily with short, three‐day bursts of potent topical corticosteroid. One trial (Sanabria‐Silva 1991), looked for 'rebound', defined as “reactivation of lesions with greater intensity than their pre‐treatment state” in the 10 days after the cessation of topical corticosteroid treatment (end of treatment was 4 weeks). No participants in either the potent topical corticosteroid group (assumed 15 participants) or mild topical corticosteroid group (assumed 15 participants) were reported as having experienced rebound.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

Six trials reported this outcome, but none of the data were suitable for pooling. The findings are summarised in Analysis 2.7. Taken together, we judged the certainty of evidence to be moderate.

Four trials measured patient‐reported itch, including 198 participants receiving potent topical corticosteroid and 205 who used mild topical corticosteroid over a range of 1 to 18 weeks (Giannetti 1981; Kirkup 2003a; Noren 1989; Thomas 2002). Although two trials were suggestive of modest improvement in itch with potent compared to mild topical corticosteroid, overall, there appeared to be little difference between the two different potencies. Similarly, there was no clinically important difference in sleep disturbance between potent and mild topical corticosteroid in two trials that included 285 participants (Kirkup 2003a; Thomas 2002), or in one trial with PGA presented as a comparison between groups (Veien 1984).

Safety: number of relevant local adverse events (primary outcome)

Nineteen trials reported local adverse events and event rates were generally low. Taken together, we judged the certainty of evidence to be low.

####### Skin thinning and related signs

Five trials that compared potent and mild topical corticosteroid of 2 to 18 weeks' duration reported the number of participants with skin thinning and related signs (Kirkup 2003a; Prado de Oliveira 2002; Ryu 1997; Thomas 2002; Vernon 1991; Analysis 2.8). Four participants of 221 who used potent topical corticosteroid reported skin thinning compared to two of 219 who used mild topical corticosteroid. Just one of the five trials, which compared daily application of a second‐generation potent topical corticosteroid to daily application of an older, mild topical corticosteroid in children with moderate to severe eczema over 42 days reported all events (Prado de Oliveira 2002).

####### Local site reactions

Eight trials that compared potent and mild topical corticosteroid of 2 to 18 weeks' duration reported the number of participants with local site reactions (Cahn 1961; Fadrhoncova 1982; Kaplan 1978; Kirkup 2003a; Prado de Oliveira 2002; Ryu 1997; Thomas 2002; Vernon 1991; Analysis 2.9). Nine of 295 participants who used potent topical corticosteroid reported local site reactions (burning, stinging, irritation, rash, itch) compared to three of 293 who used mild topical corticosteroids. One event in the mild topical corticosteroid group resulted in discontinuation from the trial (Kaplan 1978; unspecified age and severity).

####### Skin infections

Four trials that compared potent and mild topical corticosteroid of 2 to 16 weeks' duration reported the number of participants with a skin infection (Kirkup 2003a; Marten 1980; Ryu 1997; Vernon 1991; Analysis 2.10). Four of 115 participants who used potent topical corticosteroid reported skin infections (ringworm, folliculitis, eczema herpeticum, scalp infection) compared to one of 111 who used mild topical corticosteroid (secondary infection). The one Staphylococcus aureus infection of the scalp in the potent group resulted in discontinuation from the trial (Vernon 1991; children with moderate to severe eczema).

####### Other local adverse events

Two trials of six and 18 weeks' duration each reported hair growth in one participant who used potent topical corticosteroid (Prado de Oliveira 2002; Thomas 2002; 232 participants).

Safety: number of relevant systemic adverse events (secondary outcome)

Of the 16 parallel‐group trials included within this comparison, six reported on relevant systemic adverse events. Taken together, we judged the certainty of evidence to be very low.

Four trials of six days' to six weeks' duration reported the number of participants with abnormal cortisol levels (Lebrun‐Vignes 2000; Marten 1980; Queille 1984; Vernon 1991; Analysis 2.11). In the three trials that reported the number of cases, 11 of 43 children with moderate to severe eczema who used potent topical corticosteroid had abnormal cortisol levels compared to 4 of 39 children who used mild topical corticosteroid. Two trials reported that no relevant systemic adverse events occurred (Thomas 2002; Prado de Oliveira 2002; 232 participants).

Unspecified adverse events (safety)

An additional seven trials of short duration looked for adverse events but provided no information on which adverse events, specifically they investigated or whether the adverse events were local or systemic (Gentry 1973; Giannetti 1981; Sanabria‐Silva 1991; Savin 1976; Veien 1984; Wortzel 1975; Yasuda 1976; Analysis 2.12), and most reported no adverse events or no serious adverse events.

Potent versus moderate‐potency topical corticosteroid

See: Table 3.

This comparison comprises 25 trials; 12 parallel‐group (Bluefarb 1976; Busch‐Heidger 1993; Lassus 1983; Lebwohl 1999; Nolting 1991; Queille 1984; Rafanelli 1993; Rampini 1992a; Rampini 1992b; Ulrich 1991; Van Del Rey 1983; Wolkerstorfer 1998) and 13 within‐participant (Allenby 1981; Craps 1973; Cullen 1971; Henrijean 1983; Innocenti 1977; Munro 1967; Rajka 1986; Roth 1978b; Ruiz 1976; Sefton 1983a; Sefton 1983b; Sefton 1983c; Stewart 1973). In 19 trials only the potency of topical corticosteroid varied between groups (single strategy), whilst the remaining six trials were a combination of different strategies of topical corticosteroid use.

Of the six trials that tested multiple strategies, one trial compared a potent lipocream with moderate‐potency ointment (Rajka 1986). One trial compared once daily potent topical corticosteroid with twice daily moderate topical corticosteroid (Rampini 1992a). Three trials compared once daily potent second‐generation topical corticosteroid to twice daily older, moderate‐potency topical corticosteroid (Lebwohl 1999; Rafanelli 1993; Wolkerstorfer 1998). A further trial also compared once daily application of a second‐generation potent topical corticosteroid to twice daily application of an older, moderate topical corticosteroid (Nolting 1991).

Data were available for all outcomes relevant to this review.

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

All trials included in this comparison measured clinician‐reported signs of eczema. Taken together, we judged the certainty of evidence to be moderate.

####### Pooled potent versus moderate‐potency topical corticosteroid

**Investigator global assessment (IGA)**We pooled IGA as a short‐term outcome (range 1 to 3 weeks) from 15 trials (Bluefarb 1976; Craps 1973; Cullen 1971; Innocenti 1977; Lassus 1983; Lebwohl 1999; Nolting 1991; Rafanelli 1993; Rajka 1986; Rampini 1992a; Rampini 1992b; Roth 1978b; Ruiz 1976; Ulrich 1991; Van Del Rey 1983), that included 1053 participants; 933 from the parallel‐group trials and 120 from the within‐participant trials. Most trials used a 4‐, 5‐, or 6‐point scale and we pooled data from categories corresponding to ‘cleared or marked improvement’ where possible. In the parallel‐group trials, 217 of 467 participants who used potent topical corticosteroid achieved cleared or marked improvement in IGA compared to 218 of 466 in those who used moderate topical corticosteroid. In the within‐participant trials, 63 of 120 achieved cleared or marked improvement on the side treated with potent topical corticosteroid compared to 49 of 120 on the side treated with moderate topical corticosteroid. The OR was 1.33 (95% CI 0.93 to 1.89; P = 0.12; I² = 11%; 15 trials, 1173 participants or sides treated; Analysis 3.1). This is insufficient evidence to show that potent topical corticosteroid are better than moderate‐potency topical corticosteroid in the short term. The short‐term time point was the end of treatment for most trials; therefore, we did not carry out a separate end of treatment meta‐analysis.We then pooled IGA as a short‐term outcome from three trials in adults only (Nolting 1991; Rajka 1986; Ruiz 1976). The OR for achieving cleared or marked improvement in the short term was 3.43 (95% CI 0.79 to 14.86; P = 0.10; I² = 43%; 3 trials, 131 participants or sides treated; Analysis 3.2.1), indicating no evidence of a difference between potent and moderate‐potency topical corticosteroid as the 95% CI is wide and includes 1. The same analysis from six trials in children only (Lassus 1983; Lebwohl 1999; Rafanelli 1993; Rampini 1992a; Rampini 1992b; Ruiz 1976), also showed no difference (OR 1.12, 95% CI 0.50 to 2.51; P = 0.79; I² = 10%; 6 trials, 482 participants or sides treated; Analysis 3.2.2). As limited IGA data were available in participants with moderate eczema only (Cullen 1971), and severe eczema only (Cullen 1971; Ulrich 1991), and these subgroups overlapped with 9 trials in participants with moderate and severe eczema (Bluefarb 1976; Cullen 1971; Innocenti 1977; Lassus 1983; Lebwohl 1999; Rafanelli 1993; Rajka 1986; Ulrich 1991; Van Del Rey 1983), we performed a restricted analysis of IGA as a short‐term outcome including only trials of participants with moderate to severe eczema. The OR for achieving cleared or marked improvement was 1.39 (95% CI 0.86 to 2.23; P = 0.18; I² = 11%; 9 trials, 770 participants or sides treated; Analysis 3.3), in line with the overall analysis. Investigator assessment of clinical signsWe pooled investigator assessment of clinical signs as a short‐term outcome (range 6 to 7 days) from three small trials (Henrijean 1983; Queille 1984; Wolkerstorfer 1998), that included 36 participants; 33 from the parallel‐group trials and three from the within‐participant trial. The SMD was a decrease of 0.01 (95% CI −0.70 to 0.72; P = 0.98; I² = 16%; 3 trials, 39 participants or sides treated; Analysis 3.4), indicating no difference between potent and moderate‐potency topical corticosteroid. Similar results were seen at end of treatment (SMD 0.29, 95% CI −0.62 to 1.20; P = 0.54; I² = 0%; 3 trials, 21 participants or sides treated; Analysis 3.5).Two trials included children only (Queille 1984; Wolkerstorfer 1998), and none included adults only, therefore no subgroup analysis was possible with respect to age. In children, the SMD in the short term (day 6 to 7) was 0.23 (95% CI −1.14 to 1.60; P = 0.74; I² = 58%; 2 trials, 33 participants; Analysis 3.4.1); end of treatment (maximum week 4) was 0.49 (95% CI −0.87 to 1.85; P = 0.48; I² = 20%; 2 trials, 17 participants; Analysis 3.5.1). No difference was observed between groups at either time point.All three trials in Analysis 3.4 and Analysis 3.5 included participants with different eczema severities therefore no further subgroup analysis was possible.Number of participants with a greater IGA compared to the other groupWe pooled IGA, in the form of the number of participants for which each topical corticosteroid was judged to be better than the other, as a short‐term outcome (after 1 week) from two within‐participant trials in 100 participants (Munro 1967; Stewart 1973; unspecified age and severity of eczema). The clinician judged potent topical corticosteroid to be superior in 46 of 100 participants compared and moderate‐potency topical corticosteroid to be superior in 19 of 100. The OR was 3.86 (95% CI 2.42 to 6.14; P < 0.00001; I² = 0%; 2 trials, 100 participants; Analysis 3.6). The short‐term time point was the end of treatment for one of the two trials; therefore, we did not carry out a separate end of treatment meta‐analysis.Neither trial included in Analysis 3.6 specified participants’ age or baseline eczema severity, therefore no subgroup analyses were possible.Data not included in the meta‐analysesWe were unable to include four within‐participant trials in the meta‐analyses because the numerical data were incomplete. They are summarised in Analysis 3.7 (Allenby 1981; Sefton 1983a; Sefton 1983b; Sefton 1983c; 164 participants). In all trials, participants in both groups saw a clinically meaningful improvement in clinician‐reported signs, but there were no clear differences between potent and moderate‐potency topical corticosteroids. One trial that we included in SMD Analysis 3.4 and Analysis 3.5 also reported very limited follow‐up data (Wolkerstorfer 1998, included in Analysis 3.7).

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

Two trials reported this outcome (Munro 1967; Rafanelli 1993), and are summarised in Analysis 3.8. Taken together, we judged the certainty of evidence to be low.

Rafanelli 1993 reported that potent topical corticosteroid was more effective than moderate topical corticosteroid, although gave no numerical data support this. There appeared to be no difference between groups in Munro 1967.

Ruiz 1976 consulted patients when judging the IGA (see Analysis 3.1).

Safety: number of relevant local adverse events (primary outcome)

Seventeen trials looked for local adverse events (Bluefarb 1976; Busch‐Heidger 1993; Cullen 1971; Innocenti 1977; Lassus 1983; Lebwohl 1999; Nolting 1991; Rafanelli 1993; Rajka 1986; Rampini 1992a; Rampini 1992b; Roth 1978b; Sefton 1983a; Sefton 1983b; Sefton 1983c; Ulrich 1991; Van Del Rey 1983). Taken together, we judged the certainty of evidence to be low.

####### Skin thinning and related signs

Ten trials that compared potent and moderate topical corticosteroid of one to three weeks' duration looked for the number of participants with skin thinning and related signs (Cullen 1971; Innocenti 1977; Lebwohl 1999; Nolting 1991; Rafanelli 1993; Sefton 1983a; Sefton 1983b; Sefton 1983c; Ulrich 1991; Van Del Rey 1983; Analysis 3.9). There were four reports (2 per group) of skin thinning (541 participants).

####### Local site reactions

Thirteen trials that compared potent and moderate topical corticosteroid of two to five weeks' duration looked for the number of participants with local site reactions (Bluefarb 1976; Busch‐Heidger 1993; Cullen 1971; Lassus 1983; Lebwohl 1999; Rajka 1986; Rampini 1992a; Rampini 1992b; Roth 1978b; Sefton 1983a; Sefton 1983b; Sefton 1983c; Van Del Rey 1983; Analysis 3.10). The most frequently reported local site reaction was burning, reported by nine of 307 participants who used potent topical corticosteroid and six of 306 who used moderate topical corticosteroid.

####### Skin infections

Six trials that compared potent and moderate topical corticosteroid of two to three weeks' duration looked for the number of participants with skin infection (Cullen 1971; Rampini 1992a; Rampini 1992b; Sefton 1983a; Sefton 1983b; Sefton 1983c; Van Del Rey 1983; 372 participants; Analysis 3.11). One participant in each group reported secondary infection (Sefton 1984c; 31 participants; unspecified age; mild to moderate eczema). In Rampini 1992a, in children with unspecified severity eczema, one participant reported impetigo in the potent topical corticosteroid group (55 participants) compared to none in the moderate topical corticosteroid group (53 participants).

Other adverse events are described under ‘Unspecified adverse events (safety)’.

Safety: number of relevant systemic adverse events (secondary outcome)

Six parallel‐group trials looked for systemic adverse events (Queille 1984; Rafanelli 1993; Rampini 1992a; Rampini 1992b; Ulrich 1991; Wolkerstorfer 1998). Taken together, we judged the certainty of evidence to be very low.

Three trials of children with moderate to severe eczema, of six days' to four weeks' duration, reported the number of participants with abnormal cortisol levels (Queille 1984; Rafanelli 1993; Wolkerstorfer 1998; Analysis 3.12). Nine of 55 children who used potent topical corticosteroid had abnormal cortisol levels compared to one of 44 who used moderate topical corticosteroid. All nine events in the potent topical corticosteroid group were reported by Queille 1984, in which 13 children were treated with potent topical corticosteroid once daily for six days then alternate days until discharged.

Rampini 1992a, Rampini 1992b, and Ulrich 1991 reported that no systemic adverse events occurred (351 participants; week 2 to 3).

Unspecified adverse events (safety)

An additional three trials of two to five weeks' duration looked for adverse events (Busch‐Heidger 1993; Henrijean 1983; Ruiz 1976), but provided no information on specifically which adverse events they investigated or whether they were local or systemic. Two within‐participant trials reported no adverse events (Ruiz 1976 in adults and children with unspecified severity eczema; Henrijean 1983 in participants with unspecified age and severity eczema; 9 participants). Busch‐Heidger 1993 reported no serious adverse events (unspecified) up to five weeks (75 participants).

In addition to skin thinning reported above, Nolting 1991 looked for adverse events, however the trial authors report that no other significant adverse events occurred.

Very potent versus potent topical corticosteroid

See: Table 4.

This comparison comprises six trials; two parallel‐group (Harder 1983; Yawalkar 1991), and four within‐participant (Bleeker 1975; Goh 1999; Guttman‐Yassky 2017; Sparkes 1974). In four trials, only the potency of topical corticosteroid varied between groups (single strategy), whilst the remaining two trials were a combination of multiple different strategies of topical corticosteroid use.

Harder 1983 compared once daily very potent topical corticosteroid with three times daily older potent topical corticosteroid. Goh 1999 compared twice daily very potent topical corticosteroid with once daily second‐generation potent topical corticosteroid, which contrasts with most multi‐strategy trials where the higher‐potency topical corticosteroid is used less frequently, reflecting clinical practice, and so has been excluded from the meta‐analyses.

Data were available for all outcomes relevant to this review.

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

All trials included in this comparison measured clinician‐reported signs of eczema. Taken together, we judged the certainty of evidence to be low.

####### Pooled very potent versus potent topical corticosteroid

**Investigator global assessment (IGA)**We pooled IGA as a short‐term outcome (range 1 to 2 weeks) from three trials (Bleeker 1975; Harder 1983; Yawalkar 1991), that included 216 participants; 189 from the parallel‐group trials and 27 from the within participant trial (Bleeker 1975). These trials used a 4‐, 5‐, or 6‐point scale and we pooled data from categories corresponding to ‘cleared or marked improvement’ where possible. In the parallel‐group trials, 79 of 96 participants who used very potent topical corticosteroid achieved cleared or marked improvement compared to 87 of 93 who used potent topical corticosteroid. In the within‐participant trial, 25 of 27 sides achieved cleared or marked improvement with both very potent and potent topical corticosteroid. The OR was 0.53 (95% CI 0.13 to 2.09; P = 0.37, I² = 52%; 3 trials, 243 participants or sides treated; Analysis 4.1), suggesting no difference between very potent and potent topical corticosteroid. The short‐term time point was the end of treatment for two of the three trials; therefore, we did not carry out a separate end of treatment meta‐analysis. We considered repeating this analysis with the alternative threshold of ‘any improvement’ where available, to address the fact that people with severe eczema may also be interested in more modest effects. However, only one trial presented data in this way and we did not do a separate meta‐analysis.Only one trial included in Analysis 4.1 specified participants’ age and baseline eczema severity (Yawalkar 1991; adults with moderate and severe eczema), therefore no subgroup analyses were possible.Number of participants with a greater IGA compared to the other groupWe pooled IGA, in the form of the number of participants for which each topical corticosteroid was judged to be better than the other, as a short‐term outcome (one week) from four distinct sets of participants from a single within‐participant trial that included 398 participants (Sparkes 1974; age and severity unspecified). Very potent topical corticosteroid was judged to be better in 127 participants; potent topical corticosteroid was judged to be better in 83 participants. The OR for the clinician judging very potent topical corticosteroid to be superior to potent topical corticosteroid was 1.68 (95% CI 1.00 to 2.83; P = 0.05; I² = 80%; 398 participants; Analysis 4.2), suggesting very potent topical corticosteroid was more effective than potent topical corticosteroid. There was no obvious reason for the high statistical heterogeneity. There were no additional end of treatment data in this trial. The trial included in Analysis 4.2 (Sparkes 1974) did not report participants’ age or baseline eczema severity, therefore no subgroup analyses were possible.Data not included in the meta‐analysesA further two within‐participant trials were unsuitable for pooling (87 participants). One showed no difference between treatments (Guttman‐Yassky 2017); another favoured very potent topical corticosteroid (Goh 1999). However, the latter was thought clinically irrelevant as very potent topical corticosteroid was applied twice daily and potent topical corticosteroid was a second‐generation topical corticosteroid applied once daily. Results are provided in Analysis 4.3.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

One within‐participant trial measured patient‐reported effectiveness in a comparison of twice daily application of a very potent topical corticosteroid to once daily application of a second‐generation potent topical corticosteroid in 58 adults with moderate to severe eczema (Goh 1999). At day 8, the number of participants reporting an excellent response on the side treated with very potent topical corticosteroid was nine compared to three for the side treated with potent topical corticosteroid (OR 3.37, 95% 1.22 to 9.29; 1 trial, 58 participants). At day 22, 25 participants reported an excellent response on the side treated with very potent topical corticosteroid compared to six treated with potent topical corticosteroid (OR 6.57, 95% CI 3.14 to 13.74; 1 trial, 58 participants; Analysis 4.4). we judged the certainty of evidence to be very low.

Safety: number of relevant local adverse events (primary outcome)

Two trials looked for local adverse events (Goh 1999; Yawalkar 1991). Bleeker 1975 also reported local adverse events, however they did not present results for participants with atopic eczema separately for this outcome. Taken together, we judged the certainty of evidence to be very low.

####### Skin thinning and related signs

Two trials in adults with moderate and severe eczema that compared very potent and potent topical corticosteroids of two to three weeks' duration looked for the number of participants with skin thinning and related signs; none were reported (Goh 1999; Yawalkar 1991; 175 participants; Analysis 4.5).

####### Local site reactions

Yawalkar 1991 reported five local adverse events in the group that received very potent topical corticosteroid (58 participants) and two in the group that received potent topical corticosteroid (59 participants), which included dryness and itching. One participant per group discontinued because of severe dryness. Goh 1999 also stated that "no side effects were observed on any of the treated sites" (58 participants). See Analysis 4.6.

Other adverse events are described under ‘Unspecified adverse events (safety)’.

Safety: number of relevant systemic adverse events (secondary outcome)

One parallel‐group trial stated that they looked for systemic adverse events and found none (Yawalkar 1991; 117 adults with severe eczema). We judged the certainty of evidence to be very low (Analysis 4.7).

Unspecified adverse events (safety)

An additional two trials of two to three weeks' duration looked for adverse events (Harder 1983; Guttman‐Yassky 2017). Harder 1983 stated that "side effects such as intolerance have never been observed" (72 participants; unspecified age and severity of eczema; week 3). Guttman‐Yassky 2017 did not report any relevant adverse events (22 adults; mild‐ to moderate‐severity eczema; up to week 2).

Topical corticosteroid cream versus topical corticosteroid ointment

This comparison comprises seven trials; four parallel‐group (Berth‐Jones 2003; EUCTR2009‐012028‐98‐DE; Kaplan 1978; Wilson 2009), and three within‐participant trials (Cadmus 2019; Lasthein Andersen 1988; Rajka 1986). In four trials, the only comparison of interest was ointment versus cream; three used the same topical corticosteroid in both the cream and the ointment arms (Cadmus 2019; Lasthein Andersen 1988; Wilson 2009), and one compared an ointment topical corticosteroid with a different topical corticosteroid in a cream preparation (EUCTR2009‐012028‐98‐DE). The remaining trials included multiple strategy comparisons. Berth‐Jones 2003 compared a cream and ointment of the same potent topical corticosteroid at different concentrations (0.05% cream and 0.005% ointment fluticasone), either once daily or twice daily. Two trials compared different potency topical corticosteroid in ointment or cream; Kaplan 1978 compared a potent topical corticosteroid cream with a mild topical corticosteroid ointment, and Rajka 1986 compared a potent topical corticosteroid lipocream with a moderate topical corticosteroid ointment.

Data were available for all primary outcomes and for the secondary patient‐reported symptoms of eczema (effectiveness). No data were available for the secondary number of relevant systemic adverse events (safety).

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

All trials included in this comparison measured clinician‐reported signs of eczema.

Pooled topical corticosteroid cream versus topical corticosteroid ointment

**Investigator global assessment (IGA)**We pooled IGA as a short‐term outcome (week 4) from two within‐participant trials (Lasthein Andersen 1988; Rajka 1986), that included 122 participants. The trials used 5‐ and 6‐point scales, and we pooled data from categories corresponding to ‘cleared or marked improvement’. The OR was 1.65 (95% CI 0.41 to 6.60; P = 0.48; I² = 63%; 2 trials 244 sides treated; Analysis 5.1). This suggests no difference in effectiveness between cream and ointment, but there is a high degree of imprecision. As both trials only presented data for up to 4 weeks, we did not perform a separate analysis for end of treatment.We pooled only two trials that reported IGA (Analysis 5.1), therefore subgroup analyses were not possible.Data not included in the meta‐analysesWe did not include five trials in the meta‐analysis, either because we could not pool the instrument used to measure clinician‐reported signs of eczema alongside those included (Berth‐Jones 2003; Cadmus 2019; EUCTR2009‐012028‐98‐DE), or because the numerical data were incomplete (Kaplan 1978; Wilson 2009), and are summarised in Analysis 5.2. In Berth‐Jones 2003, the OR for the 9‐point, 3‐item severity score (TIS) of achieving remission of 1 or less between the cream and ointment was 1.19 (95% CI 0.60 to 2.37) for the once daily topical corticosteroid (195 participants) and 2.06 (95% CI 1.00 to 4.22) for twice daily topical corticosteroid (181 participants). There was no clinically significant difference in EASI or IGA in any of four further trials, although all were small, with a maximum of 58 participants.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

Two within‐participant trials reported PGA as a comparison between groups in children (Cadmus 2019; Lasthein Andersen 1988). Lasthein Andersen 1988 did not report any difference between lipocream and ointment by (92 participants at week 2; 88 at week 4; P = 0.5). In Cadmus 2019, nine participants thought cream was more effective compared to 16 who preferred ointment (OR 0.43, 95% CI 0.21 to 0.87; 1 trial, 39 participants; day 3‐5).

Safety: number of relevant local adverse events (primary outcome)

Six trials looked for local adverse events (Berth‐Jones 2003; Cadmus 2019; EUCTR2009‐012028‐98‐DE; Kaplan 1978; Lasthein Andersen 1988; Rajka 1986).

Skin thinning and related signs

There were no cases of skin thinning in a three‐week trial in adults (EUCTR2009‐012028‐98‐DE; Analysis 5.3). Related signs were reported in one trial at four weeks (Berth‐Jones 2003; Analysis 5.3) with one participant in each group reporting telangiectasia, and one participant who used ointment reporting striae; two of these events preceded the trial treatment, but it is unclear which (426 participants).

Local site reactions

Four trials that compared cream and ointment of one to four weeks' duration reported the number of participants with local site reactions (Cadmus 2019; EUCTR2009‐012028‐98‐DE; Kaplan 1978; Rajka 1986; Analysis 5.4). The most frequently observed local site reaction was burning, reported in a within‐participant trial by five participants treated with cream, two of whom also reported burning with ointment (Cadmus 2019; 39 participants). Burning was also reported by a participant in a parallel‐group trial, treated with ointment (Kaplan 1978). Eight participants who used cream reported other local site reactions compared to two who used ointment (55 participants from parallel‐group trials; 69 participants from within‐participant trials), one of which resulted in discontinuation from the trial (Kaplan 1978; unspecified age and severity).

Skin infection

Three trials that compared cream and ointment of one to four weeks' duration reported the number of participants with skin infection (Cadmus 2019; EUCTR2009‐012028‐98‐DE; Lasthein Andersen 1988; Analysis 5.5). No participants reported skin infection using cream (156 participants or sides treated) compared to one who used ointment (156 participants or sides treated).

Safety: number of relevant systemic adverse events (secondary outcome)

Relevant systemic adverse events were not reported in the included parallel‐group trials for this comparison.

Unspecified adverse events (safety)

One parallel‐group trial that included adults with mild‐ to moderate‐severity disease reported no adverse events (Wilson 2009; up to week 2; 6 participants in the ointment group; 8 in the lipocream group; 8 in the cream group).

Different concentrations of the same topical corticosteroid

We included two trials that compared different concentrations of the same topical corticosteroid. One trial (Dolle 2015), compared two concentrations of an experimental potent topical corticosteroid, GW870086. This cross‐over trial in 25 adults with moderate to severe eczema compared 2% (15 sites treated) versus 0.2% (20 sites treated) versions of the cream in specified lesions. An additional four‐week, multi‐arm, parallel‐group trial in adults and children with moderate to severe eczema compared 0.05% cream and 0.005% ointment preparations of the same potent topical corticosteroid (fluticasone; Berth‐Jones 2003 once daily application and Berth‐Jones 2003 twice daily application).

Different concentrations of the same topical corticosteroid

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

Dolle 2015 assessed clinical signs using the TIS, a clinical signs scale of 0 to 9, where an increase represents worsening eczema. There was no significant difference between the 0.2% and 2% GW870086 groups in the mean change in TIS from baseline at day 7 or 22, although an improvement in the signs of eczema was seen in both groups. At day 7 the mean change in the 2% group was −1.78 (95% CI −2.64 to −0.92; 15 sites treated) versus −1.43 (95% CI −2.18 to −0.67; 20 sites treated) in the 0.2% group. A further reduction by day 22 was seen, mean change of −2.49 (95% CI −3.49 to −1.49; 15 sites treated) in the 2% group and −1.99 (95% CI −2.86 to −1.12; 20 sites treated) with 0.2%. The number of treatment responses (TIS score 1 or less, irrespective of baseline score) at day 22 was 7 with 0.2% and 6 with 2%.

Berth‐Jones 2003 reported that 76 of 95 participants achieved remission (TIS ≤ 1) using 0.05% fluticasone cream compared to 77 of 100 who used 0.005% fluticasone ointment applied once daily (OR 1.19, 95% CI 0.60 to 2.37; 195 participants). When applied twice daily, 76 of 91 participants achieved remission using 0.05% fluticasone cream compared to 94 of 90 who used 0.005% fluticasone ointment (OR 2.06, 95% CI 1.00 to 4.22; 181 participants) when applied twice daily.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

None of the three trials reported patient‐reported symptoms.

Safety: number of relevant local adverse events (primary outcome)

Dolle 2015 stated that, up to week five (7 to 14 days' follow‐up), "GW870086 showed no clinical signs of atrophogenic effects in AD patients," although no values were given.

Berth‐Jones 2003 reported one case each of striae and telangiectasia in the 0.005% ointment groups (190 participants) and one case of telangiectasia in the 0.05% cream group (186 participants).

Safety: number of relevant systemic adverse events (secondary outcome)

Neither of the trials reported systemic adverse events in this strategy comparison.

Second‐generation topical corticosteroid versus older topical corticosteroid

The term 'second‐generation' refers to newer topical corticosteroids, primarily fluticasone propionate and mometasone furoate, developed in the 1990s with the intention of minimising adverse events whilst preserving effectiveness. They are marketed as once daily alternatives to standard topical corticosteroids, which were typically applied twice a day. This is reflected in the regimens and the choice of older topical corticosteroid comparators used in the included trials. There is significant overlap between this comparison and the trials included in the once versus twice daily application comparison. This comparison comprises 15 trials; 12 parallel‐group trials (Amerio 1998; Hoybye 1991; Kirkup 2003a; Kirkup 2003b; Lebwohl 1999; Marchesi 1994; Nolting 1991; Prado de Oliveira 2002; Rafanelli 1993; Ryu 1997; Vernon 1991; Wolkerstorfer 1998) and three within‐participant trials (Goh 1999; Kim 2013; Reidhav 1996).

Seven trials compared a potent second‐generation topical corticosteroid applied once daily with an older topical corticosteroid of a different potency (usually mild/moderate) used more frequently (usually twice daily; Goh 1999; Lebwohl 1999; Nolting 1991; Rafanelli 1993; Ryu 1997; Vernon 1991; Wolkerstorfer 1998). Three trials compared a potent second‐generation topical corticosteroid used once daily with the same potency older topical corticosteroid used twice daily (Amerio 1998; Hoybye 1991; Marchesi 1994). A further two trials compared the second‐generation potent topical corticosteroid with a mild‐potency older topical corticosteroid, both used once daily (Kirkup 2003a; Prado de Oliveira 2002). Only three trials were single strategy, that is, a second‐generation potent topical corticosteroid versus an older topical corticosteroid of the same potency and both applied the same number of times per day (Kim 2013; Kirkup 2003b; Reidhav 1996).

Data were available for all outcomes relevant to this review.

Second‐generation topical corticosteroid versus older topical corticosteroid

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

All trials included in this comparison measured clinician‐reported signs of eczema.

####### Pooled second‐generation topical corticosteroid versus older topical corticosteroid

**Dichotomous investigator global assessment (IGA)**We pooled IGA as a short‐term outcome (range 1 to 4 weeks) from nine parallel‐group trials (Amerio 1998; Hoybye 1991; Kirkup 2003a; Kirkup 2003b; Lebwohl 1999; Marchesi 1994; Nolting 1991; Rafanelli 1993; Ryu 1997), involving 824 participants. Most trials used a 4‐, 5‐, or 6‐point scale and we pooled data from categories corresponding to ‘cleared or marked improvement’ where possible. Overall, 251 of 383 participants achieved cleared or marked improvement when using second‐generation topical corticosteroid compared to 196 of 408 participants who used older topical corticosteroids. The OR across all single‐strategy and multiple‐strategy trials that compared a second‐generation topical corticosteroid with an older topical corticosteroid was 2.52 (95% CI 1.47 to 4.30; P = 0.0007; I² = 27%; 9 trials, 824 participants; Analysis 6.1), in favour of second‐generation topical corticosteroid. This corresponds to a need to treat 4.6 people with a second‐generation topical corticosteroid to achieve an additional treatment success compared to older topical corticosteroid (95% CI 3.1 to 10.4). We then pooled IGA from three trials in adults only (Hoybye 1991; Marchesi 1994; Nolting 1991). The OR for achieving cleared or marked improvement in adults was 1.70 (95% CI 0.88 to 3.31; P = 0.12; I² = 0%; 3 trials, 221 participants; Analysis 6.2.1), showing no difference between groups. We included four trials in children, as a short‐term outcome (Kirkup 2003a; Kirkup 2003b; Lebwohl 1999; Rafanelli 1993). The OR for achieving cleared or marked improvement in children was 2.68 (95% CI 1.07 to 6.76; P = 0.04; I² = 40%, 4 trials, 483 participants; Analysis 6.2.2), favouring second‐generation topical corticosteroid. The test for subgroup differences for Analysis 6.2 had a P value of 0.43, suggesting that the effect of second‐generation topical corticosteroid was not dependent on age.We were unable to perform subgroup analyses based on severity due to the lack of trials in participants with milder disease, which is reasonable considering that the second‐generation topical corticosteroids are potent topical corticosteroids. We restricted the previous analyses to the seven trials that reported IGA in participants with moderate to severe eczema as a short‐term outcome (range 1 to 4 weeks; Amerio 1998; Hoybye 1991; Kirkup 2003a; Kirkup 2003b; Lebwohl 1999; Marchesi 1994; Rafanelli 1993). The OR for achieving cleared or marked improvement in moderate to severe eczema was consistent with the overall estimate (OR 2.40, 95% CI 1.53 to 3.79; P = 0.0002; I² = 0%; 7 trials, 734 participants; Analysis 6.3). We also found similar results at end of treatment overall (Amerio 1998; Hoybye 1991; Lebwohl 1999; Marchesi 1994; Nolting 1991; Prado de Oliveira 2002; Rafanelli 1993; Ryu 1997); 2.79 (95% CI 1.71 to 4.56; P < 0.0001; I² = 5%; 8 trials, 580 participants; Analysis 6.4); in adults versus children (Hoybye 1991; Lebwohl 1999; Marchesi 1994; Nolting 1991; Prado de Oliveira 2002; Rafanelli 1993; P = 0.41; Analysis 6.5); and in moderate to severe eczema (range 1 to 6 weeks; Amerio 1998; Hoybye 1991; Lebwohl 1999; Marchesi 1994; Prado de Oliveira 2002; Rafanelli 1993); OR 2.74 (95% CI 1.64 to 4.58; P = 0.0001; I² = 0%; 6 trials, 490 participants; Analysis 6.6). As we had noted at data extraction that several trials were industry‐sponsored, we repeated both short‐term and end‐of‐treatment analyses of IGA data in a post‐hoc sensitivity analysis to exclude trials with obvious links to industry (Hoybye 1991; Kirkup 2003a; Kirkup 2003b; Lebwohl 1999; Marchesi 1994). The OR in the short term was 4.11 (95% CI 1.15 to 14.63; P = 0.03; I² = 40%; 247 participants; Table 15), and at end of treatment was 3.46 (95% CI 1.32 to 9.06; P = 0.01; I² = 39%; 271 participants). Removing several trials judged high risk of bias expanded the 95% CI to include 1 (see: Table 13); OR 2.12 (95% CI 0.51 to 8.81).**Mean investigator global assessment (IGA)**We pooled mean IGA in two trials (range 14 to 16 weeks that included a two‐ to four‐week acute treatment phase) in 193 children with moderate to severe eczema (Kirkup 2003a; Kirkup 2003b). MD was −1.63 (95% CI −2.57 to −0.69; P = 0.0007; I² = 0%; 2 trials, 193 participants; Analysis 6.7) in favour of second‐generation topical corticosteroid. The single strategy trial was consistent with the multiple strategy trial.As both trials that reported mean IGA at end of treatment (Analysis 6.7) included children with moderate to severe eczema only, no further restricted analysis was possible.Investigator‐assessed clinical signsWe pooled investigator assessment of clinical signs as a short‐term outcome (range 7 to 15 days) from two trials (Kim 2013; Wolkerstorfer 1998), in 180 participants; 21 from the parallel‐group trial and 159 from the within‐participant trial. The SMD was 0.16 (95% CI −0.45 to 0.77; P = 0.61; I² = 56%; 2 trials, 339 participants or sides treated; Analysis 6.8), suggesting no difference between treatments. The short‐term time point was the end of treatment for Kim 2013; therefore we did not do a separate end of treatment meta‐analysis. As we included only two trials in SMD Analysis 6.8, subgroup analyses were not possible.Data not included in the meta‐analysesWe did not include two small trials in any meta‐analyses because the numerical data were incomplete (Reidhav 1996; Vernon 1991). We have summarised these in Analysis 6.9, and neither demonstrated a difference between the second‐generation and older topical corticosteroid. We did not include another in the meta‐analyses because it was thought to be clinically incomparable owing to the use of a more potent topical corticosteroid more frequently than the less potent topical corticosteroid, however we also include the results narratively (Goh 1999). One trial that was included in SMD Analysis 6.8 also reported some limited follow‐up data (Wolkerstorfer 1998), also included in Analysis 6.9.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

####### Pooled second‐generation topical corticosteroid versus older topical corticosteroid

ItchWe pooled the number of participants who judged itch to be better as a short‐term outcome (week 2 to 4) from two parallel‐group trials that included 243 children with moderate to severe eczema (Kirkup 2003a; Kirkup 2003b). The OR at week 2 to 4 was 2.26 (95% CI 1.24 to 4.14; P = 0.008; I² = 0%; 2 trials, 243 participants; Analysis 6.10). The single strategy trial was similar to the multiple strategy trial, although the multiple strategy trial was not statistically significant. However, when we pooled the same two trials at end of treatment (week 14 to 16) the significance between groups was not maintained (OR 1.16, 95% CI 0.60 to 2.25; P = 0.67; I² = 0%; 2 trials, 193 participants; Analysis 6.11).Sleep disturbanceWe pooled the number of participants who judged sleep disturbance to be better as a short‐term outcome (week 2 to 4) from two parallel‐group trials that included 242 children with moderate to severe eczema (Kirkup 2003a; Kirkup 2003b). The OR at week 2 to 4 was 2.09 (95% CI 1.15 to 3.81; P = 0.02 I² = 0%; 2 trials, 242 participants; Analysis 6.12). The single‐strategy trial was consistent with the multiple‐strategy trial. We found similar results at end of treatment (week 14 to 16; Kirkup 2003a; Kirkup 2003b; OR 2.41, 95% CI 1.03 to 5.65; P = 0.04; I² = 19%; 2 trials, 193 participants; Analysis 6.13).Both trials that reported the number of participants who judged itch and sleep disturbance to be better (Analysis 6.10; Analysis 6.11; Analysis 6.12; Analysis 6.13), included children with moderate to severe eczema only, therefore no further restricted analysis was possible.Data not included in the meta‐analysesSix additional trials included in this comparison measured patient‐reported symptoms of eczema in some way, most were of a reasonable size (Amerio 1998; Goh 1999; Hoybye 1991; Kim 2013; Rafanelli 1993; Reidhav 1996), and are summarised in Analysis 6.14. The results are mixed, however most trials reported little or no difference between groups in itch or patient global assessment.

Safety: number of relevant local adverse events (primary outcome)

Thirteen trials looked for local adverse events (Amerio 1998; Goh 1999; Hoybye 1991; Kim 2013; Kirkup 2003a; Kirkup 2003b; Lebwohl 1999; Marchesi 1994; Nolting 1991; Prado de Oliveira 2002; Rafanelli 1993; Ryu 1997; Vernon 1991). Overall, the rate of local adverse events was low.

####### Skin thinning and related signs

Eleven trials that compared second‐generation topical corticosteroid versus older topical corticosteroid for two to six weeks reported the number of participants with skin thinning (Amerio 1998; Goh 1999; Hoybye 1991; Kirkup 2003a; Kirkup 2003b; Lebwohl 1999; Nolting 1991; Prado de Oliveira 2002; Rafanelli 1993; Ryu 1997; Vernon 1991; Analysis 6.15). Six out of 513 participants who used second‐generation topical corticosteroid reported skin thinning compared to four out of 501 participants who used older topical corticosteroid. Two trials reported all the events (Nolting 1991; Prado de Oliveira 2002), one in children and the other in adults. One trial reported related signs; there were no events in either group (Prado de Oliveira 2002; 25 participants).

####### Local site reactions

Eight trials that compared second‐generation topical corticosteroid versus older topical corticosteroid for two to 16 weeks reported the number of participants with local site burning, itching, stinging, rashes (Prado de Oliveira 2002; Kim 2013; Kirkup 2003a; Kirkup 2003b; Lebwohl 1999; Marchesi 1994; Vernon 1991; Ryu 1997; Analysis 6.16). Ten out of 497 participants who used second‐generation topical corticosteroid reported local site reactions compared to twelve out of 491 participants who used older topical corticosteroid.

####### Skin infections

Four trials that compared second‐generation topical corticosteroid versus older topical corticosteroid for two to 16 weeks' duration reported the number of participants with skin infections (Kirkup 2003a; Kirkup 2003b; Ryu 1997; Vernon 1991; Analysis 6.17). There were three reports of skin infections across the second‐generation topical corticosteroid compared with four in the control, older topical corticosteroid groups (464 participants) and there was no more than one participant per arm in each trial with an adverse event. One Staphylococcus aureus infection of the scalp in the second‐generation group resulted in discontinuation from the trial (Vernon 1991; children with moderate to severe eczema).

####### Other local adverse events

One trial, of 42 days' duration, reported hair growth in one participant who used second‐generation potent topical corticosteroid (Prado de Oliveira 2002; 25 participants).

Safety: number of relevant systemic adverse events (secondary outcome)

Seven trials reported on systemic adverse events.

Four trials of three to six weeks' duration reported on the number of participants with abnormal cortisol levels (Hoybye 1991; Rafanelli 1993; Vernon 1991; Wolkerstorfer 1998; Analysis 6.18). In the trials that provided exact numbers of participants (Rafanelli 1993; Vernon 1991;Wolkerstorfer 1998), none had abnormal cortisol in the second‐generation topical corticosteroid group (65 participants) compared to two in the older topical corticosteroid group (63 participants).

Three trials reported that no relevant systemic adverse events occurred (Kirkup 2003b; Marchesi 1994; Prado de Oliveira 2002).

Unspecified adverse events (safety)

Nolting 1991 looked for adverse events, in addition to skin thinning reported above, however, the trial authors report that no other significant adverse events occurred.

Also in addition to the skin thinning data reported above, Hoybye 1991 found that “Treatment‐related side effects were few, and these were similar in both patient groups.” These adverse events were reported to be stinging, burning, itching, dryness, acne, folliculitis, and hair growth.

Branded topical corticosteroid versus generic topical corticosteroid

We found no trials that involved the use of this strategy.

Twice or more versus once daily topical corticosteroid

See: Table 5.

This comparison comprises 25 trials; 22 parallel‐group trials (Amerio 1998; Beattie 2004; Berth‐Jones 2003; Bleehen 1995; Bryden 2009; Del Rosso 2009; Harder 1983; Hoybye 1991; Koopmans 1995; Lebwohl 1999; Marchesi 1994; Meffert 1999; Msika 2008; Nolting 1991; Rafanelli 1993; Rampini 1992a; Richelli 1990; Ryu 1997; Schlessinger 2006; Tharp 1996; Vernon 1991; Wolkerstorfer 1998), and three within‐participant trials (Goh 1999; Haneke 1992; Sudilovsky 1981). In 11 trials only the daily frequency of topical corticosteroid application varied between groups, whilst the other 14 trials included multiple strategies, for example, once daily potent topical corticosteroid versus twice daily moderate‐potency topical corticosteroid.

Nine of these 14 trials compared a newer, second‐generation potent topical corticosteroid (mometasone furoate or fluticasone propionate) applied once daily versus older topical corticosteroid applied twice daily ‐ either potent (Amerio 1998; Hoybye 1991; Marchesi 1994), moderate potency (Lebwohl 1999; Nolting 1991; Rafanelli 1993; Wolkerstorfer 1998), or mild potency (Ryu 1997; Vernon 1991). One trial compared the once daily, second‐generation potent topical corticosteroid with a stronger topical corticosteroid applied twice daily (very potent; Goh 1999), and we did no include it in any meta‐analyses on the basis that it was not clinically comparable; the more potent topical corticosteroid was used more frequently rather than less frequently. Two further trials compared either three times daily potent topical corticosteroid with once daily very potent topical corticosteroid (Harder 1983), or twice daily moderate‐potency topical corticosteroid with once daily use of a potent topical corticosteroid (Rampini 1992a); both used older topical corticosteroid. The remaining two trials compared once daily mild topical corticosteroid applied under wet wraps with twice daily application without occlusion (Beattie 2004; Bryden 2009 which used twice daily application in the control group in the first week).

Data were available for all outcomes relevant to this review.

Twice or more versus once daily topical corticosteroid

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

All trials included in this comparison measured clinician‐reported signs of eczema. Taken together, we judged the certainty of evidence to be moderate.

####### Pooled twice or more versus once daily topical corticosteroid

**Investigator global assessment (IGA)**We pooled IGA as a short‐term outcome (range 1 to 4 weeks) from 15 trials (Amerio 1998; Bleehen 1995; Del Rosso 2009; Harder 1983; Hoybye 1991; Koopmans 1995; Lebwohl 1999; Marchesi 1994; Nolting 1991; Rafanelli 1993; Rampini 1992a; Ryu 1997; Schlessinger 2006; Sudilovsky 1981; Tharp 1996), that included 1821 participants; 1672 from the parallel‐group trials and 149 from the within‐participant trial. Most trials used a 4‐, 5‐, or 6‐point scale and we pooled data from categories corresponding to ‘cleared or marked improvement’ where possible. In the parallel‐group trials, 538 of 824 participants who applied topical corticosteroid twice daily achieved cleared or marked improvement compared to 553 of 848 in the once daily group. In the within‐participant trial, 87 of 149 achieved cleared or marked improvement on the side treated with twice daily topical corticosteroid compared to 80 of 149 on the side treated with once daily topical corticosteroid. The OR across all single‐strategy and multiple‐strategy trials in which frequency of daily application differed between groups was 0.97 (95% CI 0.68 to 1.38; P = 0.86; I² = 45%; 15 trials, 1970 participants or sides treated; Analysis 7.1), indicating no benefit in applying topical corticosteroid more than once daily. Meta‐analysis of trials where the only difference between the groups was the frequency of application also showed no benefit of more frequent application (Analysis 7.1.1 and Analysis 7.1.2). However, there was more variation across trials comparing multiple strategies. As for the single strategy trials, twice daily moderate‐potency topical corticosteroid versus once daily potent topical corticosteroid (either newer second‐generation or older; Analysis 7.1.5 and 7.1.6) showed no difference between once and twice daily application. However, once daily potent second‐generation topical corticosteroid was more effective than twice daily application of equivalent potency older topical corticosteroid (Analysis 7.1.3). Ryu 1997 found once daily potent second‐generation topical corticosteroid was more effective than mild topical corticosteroid applied twice a day (Analysis 7.1.4; 23 participants) whilst Harder 1983 found that very potent topical corticosteroid applied once daily was less effective than potent topical corticosteroid applied three times daily (Analysis 7.1.7). Both Ryu 1997 and Harder 1983 were small trials with wide confidence intervals.The short‐term time point was the end of treatment for most trials; therefore, we did not do a separate end of treatment meta‐analysis. We then pooled IGA from four trials in adults only (Del Rosso 2009; Hoybye 1991; Marchesi 1994; Nolting 1991), and four trials in children only (Lebwohl 1999; Rafanelli 1993; Rampini 1992a; Schlessinger 2006). The OR for achieving cleared or marked improvement in the short term in adults was 0.77 (95% CI 0.51 to 1.17; P = 0.23; I² = 0%; 4 trials, 432 participants; Analysis 7.2.1) and in children 0.79 (95% CI 0.32 to 1.94; P = 0.61; I² = 0%, 4 trials, 478 participants; Analysis 7.2.2). We were unable to perform subgroup analyses based on severity owing to the lack of trials in participants with milder disease. Therefore, we performed a restricted analysis of nine parallel‐group trials that reported IGA in participants with moderate to severe eczema as a short‐term outcome (Amerio 1998; Bleehen 1995; Del Rosso 2009; Hoybye 1991; Lebwohl 1999; Marchesi 1994; Rafanelli 1993; Schlessinger 2006; Tharp 1996). The OR for achieving cleared or marked improvement was 0.93 (95% CI 0.65 to 1.34; P = 0.71; I² = 19%; 9 trials, 1254 participants; Analysis 7.3), indicating that for people with more severe eczema, there is no benefit in applying topical corticosteroid more than once daily. IGA data were available after two weeks' follow‐up from two parallel‐group trials, with 163 participants included in the twice daily topical corticosteroid group and 170 included in the once daily group (Del Rosso 2009; Schlessinger 2006). Ninety‐eight of 163 participants who applied topical corticosteroid twice daily achieved cleared or marked improvement compared to 83 of 170 in the once daily group. The OR was 1.58 (95% CI 0.80 to 3.10; P = 0.19; I² = 41%; 2 trials, 333 participants; Analysis 7.4), in line with the lack of difference between groups during treatment. **Investigator assessment of clinical signs **We pooled investigator assessment of clinical signs as a short‐term outcome (week 1) from two trials in 40 children with moderate‐severity eczema (Wolkerstorfer 1998; Beattie 2004). The once daily group in Beattie 2004 applied the mild topical corticosteroid under wet wraps. The SMD in the short term (week 1) was a decrease of 0.40 (95% CI −0.23 to 1.03; P = 0.21; I² = 0%; 2 trials, 40 participants; Analysis 7.5), indicating no benefit from applying topical corticosteroid more than once daily in children with moderate to severe eczema. Similar results were found at end of treatment (2 to 4 weeks; SMD 0.51, 95% CI −0.32 to 1.33; P = 0.23; I² = 0%; 2 trials, 24 participants; Analysis 7.6).As all trials included in SMD Analysis 7.5 and Analysis 7.6 included children with moderate‐severity eczema only, no further subgroup analyses were possible.Data not included in the meta‐analysesEight trials were not included in any meta‐analyses either because the instrument used to measure clinician‐reported signs of eczema could not be pooled with those included (Berth‐Jones 2003; Bryden 2009), because the numerical data were incomplete (Haneke 1992; Meffert 1999; Msika 2008; Richelli 1990; Vernon 1991), or because the trial was judged not clinically comparable owing to the more potent topical corticosteroid being used more frequently than the less potent topical corticosteroid (Goh 1999). These have been summarised in Analysis 7.7 and are generally consistent with no difference between groups (879 participants). Two trials that were included in SMD Analysis 7.5 and Analysis 7.6 also reported some limited follow‐up data (Beattie 2004; Wolkerstorfer 1998), also included in Analysis 7.7.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

Eleven trials included in this comparison measured patient‐reported symptoms of eczema. Taken together, we judged the certainty of evidence to be low.

####### Pooled twice or more versus once daily topical corticosteroid

We pooled PGA as a short‐term outcome (range 1 to 4 weeks) from two trials (Koopmans 1995; Tharp 1996). The trials used a 4‐ or 6‐point scale and we pooled data from categories corresponding to ‘cleared or marked improvement’ where possible. In the group treated with twice daily topical corticosteroid 128 of 151 achieved cleared or marked improvement; 114 of 149 participants achieved cleared or marked improvement in the once daily topical corticosteroid group. The OR was 1.91 (95% CI 0.62 to 5.83; P = 0.26; I² = 67%; 2 trials, 300 participants; Analysis 7.8). The short‐term time point was the end of treatment for one of the two trials; therefore, we did not do a separate end of treatment meta‐analysis.

Both trials that reported PGA included adults and children, and only one of these gave baseline severity of eczema; therefore, no subgroup or restricted analyses were possible.

####### Data not included in the meta‐analyses

We did not include nine trials in the meta‐analyses, either because the instrument used to measure clinician‐reported signs of eczema could not be pooled alongside those included, because the numerical data were incomplete, or because we judged the comparison not clinically comparable. We have summarised these in Analysis 7.9 and they are generally consistent with no difference between groups.

Safety: number of relevant local adverse events (primary outcome)

Nineteen trials looked for local adverse events (Amerio 1998; Beattie 2004; Berth‐Jones 2003; Bleehen 1995; Del Rosso 2009; Goh 1999; Haneke 1992; Hoybye 1991; Koopmans 1995; Lebwohl 1999; Marchesi 1994; Nolting 1991; Rafanelli 1993; Rampini 1992a; Ryu 1997; Schlessinger 2006; Sudilovsky 1981; Tharp 1996; Vernon 1991). Meffert 1999 also reported local adverse events, however, they did not present data separately for the comparison of interest. Taken together, we judged the certainty of evidence to be low.

####### Skin thinning and related signs

Twelve trials that compared twice or more versus once daily application of topical corticosteroid for two to six weeks reported skin thinning or related signs (Amerio 1998; Berth‐Jones 2003; Del Rosso 2009; Goh 1999; Haneke 1992; Hoybye 1991; Lebwohl 1999; Nolting 1991; Rafanelli 1993; Ryu 1997; Schlessinger 2006; Vernon 1991; Analysis 7.10). Trials reported skin thinning in 10 participants in both the twice or more times daily group (706 participants) and the once daily topical corticosteroid group (717 participants; Analysis 7.10.1). Eight of these were reported in two trials, which both used very potent topical corticosteroid (Del Rosso 2009; Schlessinger 2006). Three trials reported on clinical signs relating to skin thinning although it is unclear whether multiple signs were experienced by the same participants. Berth‐Jones 2003 reported that one participant experienced striae and two reported telangiectasia. However, two of the three events preceded the start of trial treatment, and it is unclear which, so we have not included this trial in any subsequent summary statistics.

####### Local site reactions

Eight trials that compared twice or more versus once daily application of topical corticosteroid for four to six weeks reported the number of participants with local site reactions (Bleehen 1995; Koopmans 1995; Lebwohl 1999; Marchesi 1994; Rampini 1992a; Sudilovsky 1981; Tharp 1996; Vernon 1991; Analysis 7.11). Haneke 1992 also reported local site reactions, however, they did not present data separately for each comparison of interest. Across the trials that gave exact numbers of participants, almost all trials reported at least one event, with the largest number of participants reporting irritation in Bleehen 1995 (2/133 in the twice daily group; 5/137 in the once daily group, both treated with second‐generation topical corticosteroid). Overall, 651 participants were treated with twice (or more) daily topical corticosteroid and 655 with once daily topical corticosteroid.

####### Skin infection

Five trials that compared twice or more versus once daily application of topical corticosteroid for two to six weeks' duration reported the number of participants with skin infection (Beattie 2004; Koopmans 1995; Rampini 1992a; Ryu 1997; Vernon 1991; Analysis 7.12). Haneke 1992 also reported skin infections, however, they did not present data separately for each comparison of interest. One participant who used twice daily topical corticosteroid reported folliculitis (174 participants) compared to seven participants who reported folliculitis and one who reported impetigo contagiosa in the once daily group (175 participants). One Staphylococcus aureus infection of the scalp in the once daily topical corticosteroid group was stated to have resulted in discontinuation from the trial (Vernon 1991; children with moderate to severe eczema).

####### Other local adverse events

In addition, Goh 1999 reported no other local adverse events up to day 22 (within‐participant trial; 58 participants). Other adverse events are described under ‘Unspecified adverse events (safety)’.

Safety: number of relevant systemic adverse events (secondary outcome)

Ten parallel‐group trials looked for systemic adverse events. Meffert 1999 also reported systemic adverse events, however, they did not present data separately for each group. Taken together, we judged the certainty of evidence to be very low.

Seven trials of one to six weeks' duration measured abnormal cortisol levels (Del Rosso 2009; Hoybye 1991; Rafanelli 1993; Richelli 1990; Schlessinger 2006; Vernon 1991; Wolkerstorfer 1998; Analysis 7.13). Across the four trials that gave exact numbers of participants, five events were reported in 124 children with moderate to severe eczema who used twice daily topical corticosteroid compared to none in 125 who used once daily topical corticosteroid. Three trials reported that no relevant systemic adverse events occurred (Berth‐Jones 2003; Marchesi 1994; Rampini 1992a; 544 participants).

Unspecified adverse events (safety)

An additional trial (Harder 1983), looked for adverse events. None were reported (up to week 3; 72 participants).

Nolting 1991 looked for adverse events, in addition to skin thinning reported above, however the trial authors report that no other significant adverse events occurred. Also, in addition to the skin thinning data reported above, Hoybye 1991 found that “Treatment‐related side effects were few, and these were similar in both patient groups.” These adverse events were reported to be stinging, burning, itching, dryness, acne, folliculitis, and hair growth.

Daily application versus less frequent application

This comparison is focused on comparing different number of days per week topical corticosteroids are applied for treating eczema. This differs from the daily frequency comparison, which compared different number of applications per day, assuming daily application, and from the weekend (proactive) therapy comparison, in which a defined two days per week of treatment is used for preventing flares. This comparison comprises four trials; three parallel‐group trials (Msika 2008; Sillevis 2000; Thomas 2002), and one within‐participant trial (Mahrle 1989). Two trials compared daily application with application only on alternate days, two‐day intervals between applications, or three‐day intervals (Mahrle 1989; Msika 2008). Two trials compared daily application with application only on three to four consecutive days of each week (Sillevis 2000; Thomas 2002). Thomas 2002 compared mild topical corticosteroid used for seven days to a three‐day ‘pulse’ of potent topical corticosteroid for management of flares.

Data were available for all primary outcomes and for the secondary patient‐reported symptoms of eczema (effectiveness). No data were available for the secondary number of relevant systemic adverse events (safety).

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

All four included trials for this comparison reported this outcome and we summarised the results narratively in Analysis 8.1. There was no difference in clinical signs of eczema between daily and less frequent application (i.e. one day in every 2 to 3 days) although this was across a low number of participants; 44 in a within‐participant trial (Mahrle 1989), and 36 in a parallel‐group trial (Msika 2008). However, there were clinically significant improvements in signs of eczema in both groups. Of the two trials that compared daily application with a three‐ to four‐day ‘pulse’, one suggested that pulse treatment with moderate or potent topical corticosteroid is as effective as everyday use of moderate or mild topical corticosteroid, and that both strategies result in clinically significant improvements signs of eczema (Thomas 2002; 87 participants in both groups), and one suggested that ‘pulse’ treatment might be more beneficial, however this trial was very small (Sillevis 2000; 20 participants).

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

One trial in children with mild to moderate eczema showed no difference in itch between seven days of mild topical corticosteroid and a three‐day ‘pulse’ of potent topical corticosteroid (Thomas 2002). The median number of scratch‐free days was 118 (interquartile range (IQR) 99.8 to 124.0; 98 participants) and 117.5 (IQR 99.3 to 125.0; 100 participants) respectively, a difference of 0.5 days (95% CI −3.0 to 2.0, P = 0.68) over 18 weeks. Furthermore, there was no significant difference in sleep a subgroup of participants. The median number of undisturbed nights was 123 (IQR 109.5 to 126.0; 81 participants) in the daily topical corticosteroid group compared to 121 (IQR 101.3 to 126.0; 84 participants) in the ‘pulse’ group, a difference of two nights (95% CI 0.0 to 2.0, P = 0.53) over 18 weeks.

Safety: number of relevant local adverse events (primary outcome)

Thomas 2002 reported no cases of clinically significant skin thinning in either group up to 18 weeks (daily mild topical corticosteroid 104 participants; 3‐day potent topical corticosteroid ‘pulse’ 103 participants). Two participants in the ‘pulse’ group, who used potent topical corticosteroid for three days per week, reported spots/rash, and one reported hair growth. No other adverse events were reported.

Safety: number of relevant systemic adverse events (secondary outcome)

None of the trials included in this comparison reported any relevant systemic adverse events.

Unspecified adverse events (safety)

One small trial (27 participants) of moderate‐potency topical corticosteroid in children with moderate to severe eczema reported 20 non‐specified, non‐serious adverse events in both the daily application and the four‐days‐per‐week groups up to week 12 (Sillevis 2000; unpublished data).

Longer‐ versus shorter‐term duration of use for induction of remission

See: Table 6.

We did not find any trials that involved the use of this strategy.

Topical corticosteroid alternating with topical calcineurin inhibitor versus topical corticosteroid alone

We included only one trial (Sikder 2005), that compared topical corticosteroid alternating with topical calcineurin inhibitor (15 participants) versus topical corticosteroid alone (15 participants). This parallel‐group, short‐term trial in children aged 7 to 15 years old with moderate to severe eczema compared a moderate‐potency topical corticosteroid in the morning and 0.03% tacrolimus ointment in the evening (alternating group) versus a moderate‐potency topical corticosteroid applied twice daily. Treatment for continued for four weeks, with two weeks' follow‐up.

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

This trial combined EASI (scale of 0 to 72, increase represents worsening eczema) with a patient assessment of itching. Both groups showed significant improvement in eczema at week 4 in this composite outcome; median reduction (representing an improvement) in modified EASI from baseline was 98.7% in the alternating group (15 participants) compared to 95.1% in the group who received topical corticosteroid alone (14 participants). Median increase in adjusted EASI score at two weeks after treatment was stopped was 7.9% in the alternating group (14 participants) compared to 20.6% in the group who received topical corticosteroid alone (14 participants).

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

Sikder 2005 incorporated the patient‐reported outcome of itch into the clinician‐reported adjusted EASI score above and did not report it separately.

Safety: number of relevant local adverse events (primary outcome)

Two cases of burning were identified in the alternating group (15 participants) compared to one in the topical corticosteroid alone group (15 participants). One case of itching was reported in the alternating group (15 participants) compared to two in the topical corticosteroid alone group (15 participants).

Safety: number of relevant systemic adverse events (secondary outcome)

There was one case of fever in each group and the trial authors stated, "This event did not suggest a relationship with treatment regimes". No other systemic adverse events were reported over the six‐week trial period.

Weekend therapy versus no topical corticosteroid/reactive application

See: Table 7.

This comparison comprises nine parallel‐group trials (Berth‐Jones 2003; Fukuie 2012; Fukuie 2016; Glazenburg 2009; Hanifin 2002; Liu 2018; Peserico 2008; Rubio‐Gomis 2018; Van Der Meer 1999). Most trials used fluticasone propionate in the topical corticosteroid strategy arm; Peserico 2008 used methylprednisolone aceponate; Fukuie 2016 used betamethasone valerate. All trials were long term; each had a two‐ to four‐week acute treatment phase for flare control and most then proceeded to a 16‐ to 20‐week maintenance phase. In Fukuie 2012, maintenance was six months (assuming participants were treated throughout) and in Fukuie 2016, maintenance was 12 months. Two trials included a follow‐up  Liu 2018 for an additional 12 weeks and Hanifin 2002 for 24 weeks (although this was only in participants in the weekend therapy group who did not relapse).

Data were available for all outcomes relevant to this review.

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

Eight trials included in this comparison measured clinician‐reported signs of eczema. Taken together, we judged the certainty of evidence to be moderate.

Pooled weekend therapy versus no topical corticosteroid/reactive application

Time to relapseWe included seven trials that reported time to relapse (Berth‐Jones 2003; Glazenburg 2009; Hanifin 2002; Liu 2018; Peserico 2008; Rubio‐Gomis 2018; Van Der Meer 1999), with 621 participants in the weekend therapy group and 528 in the no topical corticosteroid/reactive application group. Definitions of relapse are included in Analysis 9.11. The hazard ratio (HR) for time to relapse was 2.28 (95% CI 1.88 to 2.76; P < 0.00001; I² = 0%; 7 trials, 1149 participants; Analysis 9.1), in favour of weekend therapy. We were unable to perform subgroup analyses of trials in adults compared to children owing to the lack of trials in adults only, so we restricted the previous analysis to children. We pooled time to relapse from three trials (Glazenburg 2009; Liu 2018; Rubio‐Gomis 2018), with 119 participants in the weekend therapy group and 112 in the no topical corticosteroid/reactive application group. The HR was 2.87 (95% CI 1.90 to 4.34; P < 0.00001; I² = 0%; 3 trials, 231 participants; Analysis 9.2), in favour of weekend therapy. We then pooled time to relapse from five trials in 993 participants with moderate to severe eczema (Berth‐Jones 2003; Glazenburg 2009; Hanifin 2002; Peserico 2008; Van Der Meer 1999). The HR was 2.12 (95% CI 1.73 to 2.60; P < 0.00001; I² = 0%; 5 trials, 993 participants; Analysis 9.3.1), in favour of weekend therapy. We also pooled two trials in 156 participants with mild‐ to moderate‐severity eczema (Liu 2018; Rubio‐Gomis 2018). The HR was 3.50 (95% CI 2.04 to 6.00; P < 0.00001; I² = 0%; 2 trials, 156 participants; Analysis 9.3.2), also in favour of weekend therapy. Number of participants with one or more relapsesWe included seven trials that reported the number of participants with one or more relapses (Berth‐Jones 2003; Glazenburg 2009; Hanifin 2002; Liu 2018; Peserico 2008; Rubio‐Gomis 2018; Van Der Meer 1999), with 621 participants in the weekend therapy group and 528 in the no topical corticosteroid/reactive application group. The risk ratio (RR), the statistic chosen to be comparable with the previous analysis by Schmitt 2011, for relapse was 0.43 (95% CI 0.32 to 0.57; P < 0.00001; I² = 67%; 7 trials, 1149 participants; Analysis 9.4), in favour of weekend therapy. This corresponds to a number needed to treat for an additional beneficial outcome of 3.0 with weekend therapy to prevent a relapse compared to no topical corticosteroid/reactive application (95% CI 2.6 to 4.0).Two trials reported number of participants with one or more relapses in 171 adults (Hanifin 2002; Van Der Meer 1999). The RR was 0.42 (95% CI 0.24 to 0.75; P = 0.003 I² = 59%; 2 trials, 171 adults; Analysis 9.5.1). Four trials reported number of participants with one or more relapses in 462 children (Glazenburg 2009; Hanifin 2002; Liu 2018; Rubio‐Gomis 2018). The RR was 0.39 (95% CI 0.24 to 0.62; P < 0.00001; I² = 68%; 4 trials, 462 children; Analysis 9.5.2).We then pooled number of participants with one or more relapses from five trials that included 993 participants with moderate to severe eczema (Berth‐Jones 2003; Glazenburg 2009; Hanifin 2002; Peserico 2008; Van Der Meer 1999). The RR was 0.46 (95% CI 0.35 to 0.61; P < 0.00001; I² = 61%; 5 trials, 993 participants; Analysis 9.6.1), in favour of weekend therapy. Two trials in 156 participants with mild‐ to moderate‐severity eczema were also included (Liu 2018; Rubio‐Gomis 2018). The RR was 0.23 (95% CI 0.04 to 1.24; P = 0.09; I² = 84%; 2 trials, 156 participants; Analysis 9.6.2), also in favour of weekend therapy. We noted at data extraction that several trials were industry‐sponsored. However, we did not conduct a post‐hoc sensitivity analysis excluding trials with obvious links to industry as this resulted in insufficient trials for pooling. Five trials were sponsored by Glaxo Wellcome (Berth‐Jones 2003; Glazenburg 2009; Hanifin 2002; Liu 2018; Van Der Meer 1999), and one was sponsored by Intendis GmbH (Peserico 2008).Data not included in the meta‐analysesFukuie 2016 reported median change in SCORAD, so we were unable to pool it. They made observations after three months and again after 12 months in children with moderate to severe eczema (30 children; 15 in each arm). After three months, median change was 42.6 (IQR 31.7 to 50.7) in the weekend therapy arm compared to 28.5 (IQR 18.3 to 39.7) in the reactive application arm. After 12 months, median change was 46.9 (IQR 38.7 to 57.2) in the weekend therapy arm compared to 36.1 (IQR 16.1 to 41.8) in the reactive application arm (P = 0.018). We extracted data using  WebPlotDigitizer. Liu 2018 reported follow‐up data at week 32 in children with mild to moderate eczema. Risk of relapse was 5.0 higher (2.4 to 10.1; 54 children vs 53; P < 0.0001) in children just using emollient.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

Four trials reported this outcome, summarised in Analysis 9.7. Trials reported results for itch (Peserico 2008; Rubio‐Gomis 2018), sleep (Peserico 2008; Rubio‐Gomis 2018), and PGA (Hanifin 2002; Liu 2018). The two trials that reported itch measures both favoured weekend therapy (270 participants). One trial that reported a sleep measure gave unclear findings (Rubio‐Gomis 2018; 49 participants), whilst another stated that it favoured weekend therapy (Peserico 2008; 221 participants).

One trial (Hanifin 2002), reported the number of participants who judged their eczema to be excellent or 163 of 225 judged their eczema to be excellent or good in the weekend therapy group; 38 of 118 judged their eczema to be excellent or good in the vehicle group. The risk ratio for adults and children at end of treatment (week 20 + 4 weeks acute phase) was 2.25 (95% CI 1.71 to 2.96; 343 participants). One further trial that reported PGA (Liu 2018), was unsuitable for pooled analysis (107 participants) as it was unclear what statistic they reported.

Taken together, we judged the certainty of evidence to be moderate.

Safety: number of relevant local adverse events (primary outcome)

Eight trials looked for local adverse events (Berth‐Jones 2003; Fukuie 2016; Glazenburg 2009; Hanifin 2002; Liu 2018; Peserico 2008; Rubio‐Gomis 2018; Van Der Meer 1999). Taken together, we judged the certainty of evidence to be low.

Skin thinning and related signs

Seven trials looked for the number of participants with skin thinning and related signs and reported no cases (1050 participants; 572 with weekend therapy and 478 without; Analysis 9.8). Glazenburg 2009 reported one participant with telangiectasia, described as “pre‐atrophy”, in each group (75 participants).

Skin infection

Two trials of participants with moderate to severe eczema reported the number of participants with skin infection (Fukuie 2016; Hanifin 2002; Analysis 9.9). Hanifin 2002 reported one participant with acne in the weekend therapy group (229 adults and children; up to 20 weeks) and none in the placebo group (119 participants). Fukuie 2016 reported one participant with eczema herpeticum in both groups (both groups with 15 participants; children only; up to 12 months). Fukuie 2016 also reported four cases of impetigo contagiosa in the weekend therapy group compared to three in the ‘as required’ group. It might be speculated that such a high number in both arms could be due to occlusive properties of the emollient used.

Other local adverse events

Two additional trials in children with mild to moderate eczema reported no local adverse events (Liu 2018, 106 participants; Rubio‐Gomis 2018, 49 participants). Rubio‐Gomis 2018 looked for hypertrichosis and found no cases.

Safety: number of relevant systemic adverse events (secondary outcome)

Eight trials looked for systemic adverse events. We judged the certainty of evidence to be very low.

Five trials reported the number of participants with abnormal cortisol levels (Fukuie 2012; Fukuie 2016; Glazenburg 2009; Hanifin 2002; Van Der Meer 1999; Analysis 9.10). Hanifin 2002 reported one participant in each group with abnormal cortisol levels, however it was unclear how many participants in each group they assessed for this outcome, and they stated that both were not newly observed.

Three trials reported no relevant systemic adverse events (Berth‐Jones 2003; Liu 2018; Rubio‐Gomis 2018; 531 participants).

Timing of application of topical corticosteroid

Two trials investigated whether the time of day that topical corticosteroids are applied had any effect. One trial in adults and children with at least moderate‐severity eczema was nested within a larger trial of twice versus once daily application (Bleehen 1995); the once daily group were also randomised to morning or night topical corticosteroid application (137 participants). Another trial of seven days' duration (Richelli 1990), in children with eczema of unspecified severity, compared application of moderate‐potency topical corticosteroid twice daily at 8 am and 3 pm (13 participants; morning/afternoon group) to application at 3 pm and 8 pm (8 participants; afternoon/evening group).

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

Bleehen 1995 reported no difference between morning and evening topical corticosteroid application at week 4, however they did not provide any numerical data (137 participants). Richelli 1990 reported investigator‐assessed signs on a scale of 0 (none) to 3 (severe) at baseline and end of treatment (day 7). At baseline, the mean was 1.27 in the morning/afternoon group and 1.24 in the afternoon/evening group. At day 7, these decreased to 0.25 in the morning/afternoon group, and 0.14 in the afternoon/evening group; dispersion data were given.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

Richelli 1990 reported mean score of symptoms of eczema as judged by participants at baseline and end of treatment (day 7). Mean score decreased from 1.17 to 0.3 in the morning/afternoon group and from 0.96 to 0.36 in the afternoon/evening group. Bleehen 1995 did not report patient‐reported data with respect to timing of topical corticosteroid application.

Safety: number of relevant local adverse events (primary outcome)

Richelli 1990 did not report this outcome, and Bleehen 1995 did not report local adverse events with respect to timing of topical corticosteroid application.

Safety: number of relevant systemic adverse events (secondary outcome)

Bleehen 1995 did not report this outcome. Richelli 1990 measured cortisol and ACTH concentrations at baseline and day 7, 8 am and 4 pm. Trial authors reported no difference in serum cortisol and ACTH after treatment relative to baseline in any of the three groups, however there was insufficient information to judge changes in individual participants' levels (assumed 30 participants; children; unclear severity of eczema).

Wet wrap versus no wet wrap

This comparison relates to the use of topical corticosteroid under occlusion (wet wrap) compared with no occlusion. It comprises six trials; five parallel‐group (Beattie 2004; Bryden 2009; Hindley 2006; Murphy 2003; Pei 2001), and one within‐participant trial (Foelster‐Holst 2006). In four trials, the only variation between groups was whether they used wet wraps (Foelster‐Holst 2006; Hindley 2006; Murphy 2003; Pei 2001), whilst the remaining two trials also varied the frequency of topical corticosteroid application (Beattie 2004; Bryden 2009). Most trials used mild topical corticosteroid in both arms; one trial used moderate topical corticosteroid (Foelster‐Holst 2006); one used a second‐generation potent topical corticosteroid (Pei 2001).

Data were available for all primary outcomes and for the secondary patient‐reported symptoms of eczema (effectiveness). No data were available for the secondary number of relevant systemic adverse events (safety).

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

All trials included in this comparison measured clinician‐reported signs of eczema.

Pooled wet wrap versus no wet wrap

We pooled investigator assessment of clinical signs as a short‐term outcome (range 2 to 3 days to 4 weeks) from three trials that used SCORAD or SASSAD (Beattie 2004; Foelster‐Holst 2006; Hindley 2006). Two parallel‐group trials included 64 participants; one within‐participant trial included 24 participants. The SMD in the short term (ranging from day 2 to week 4) was −0.26 (95% CI −0.92 to 0.41; P = 0.45; I² = 71%; 3 trials, 112 participants or sides treated; Analysis 10.1), suggesting no clinically significant benefit from using wet wraps. The high statistical heterogeneity prompted an exploration of the trial characteristics; Hindley 2006 reported several withdrawals from the wet‐wraps group (5/28) relative to the group that did not use wet wraps (0/22), and discontinued recruitment earlier than planned owing to an interim analysis concluding “clinically significant adverse differences between the two groups”. It might be speculated that this relates to the number of participants who required antibiotics in the group using wet wraps (5/23), assumed to be treating skin infections. When removing Hindley 2006, the statistical heterogeneity falls (I² = 0%) and the SMD becomes −0.60 (95% CI −1.00 to −0.21; P = 0.003), favouring topical corticosteroid use without wet wraps. The short‐term time point was the end of treatment for two of the trials, therefore we did not do a separate end of treatment meta‐analysis.

We then restricted the analysis to two trials in children only (Beattie 2004; Hindley 2006). The SMD in the short term was 0.00 (95% CI −0.79 to 0.80; P = 1.00; I² = 54%; 2 trials, 64 participants; Analysis 10.2), in line with the analysis of adults and children.

As there was overlap in the severity bandings for the trials that had specified baseline severity of eczema, no subgroup analysis relating to severity was possible.

Data not included in the meta‐analyses

We did not include three trials in any meta‐analyses because the numerical data were unsuitable for pooling (Bryden 2009; Murphy 2003; Pei 2001), and are summarised in Analysis 10.3. In line with the Analysis 10.1, Bryden 2009 found no significant difference in SASSAD between groups in a small trial of 51 children with moderate to severe eczema. One multiple arm trial of 40 children with moderate to severe eczema, who used a newer, second‐generation potent topical corticosteroid (Pei 2001), showed improvement in clinical signs in all groups, but baseline severity differed significantly between the groups making it difficult to draw any meaningful conclusion. One trial suggested an improvement in clinical signs in the wet‐wraps group but provided no numerical data to support this statement (Murphy 2003).

One trial in children with moderate‐severity eczema reported limited follow‐up data (Beattie 2004). At one week of follow‐up (week 3), SASSAD had increased in the twice daily, without wet‐wraps group to 22.8 (9 participants) and to 21.9 in the once daily, wet‐wrap group (10 participants). Beattie 2004 did not report dispersion data at this time point.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

Two trials reported itch and sleep data and we have summarised them in Analysis 10.4 (Beattie 2004; Hindley 2006). These trials included a very low number of participants (19 and 45 respectively) but there were no relevant differences suggestive of benefit in using wet wraps.

Safety: number of relevant local adverse events (primary outcome)

Two small short‐term trials in children with moderate and severe eczema (Beattie 2004; Hindley 2006; Analysis 10.5), found that seven of 33 participants treated with wet wraps reported skin infections or required antibiotics whilst none were reported in the group that did not use wet wraps (31 participants).

None of the trials included under this comparison reported skin thinning and related signs, and local site reactions.

Safety: number of relevant systemic adverse events (secondary outcome)

Relevant systemic adverse events were not reported.

Unspecified adverse events (safety)

Foelster‐Holst 2006 reported that no adverse events occurred up to end of treatment (48 to 72 hours) in the 14‐day follow‐up period (adults and children; mild to moderate eczema; 24 participants).

Topical corticosteroid applied to wet versus dry skin

Only one parallel‐group trial (Kohn 2016), compared the application of topical corticosteroid to wet skin versus dry skin. This two‐week trial in children aged two weeks to 18 years with mild to severe eczema (baseline EASI 2.8 to 34.95), compared a potent topical corticosteroid ointment applied twice daily to either dry skin (23 participants) at least 15 minutes after a bath or shower or wet skin (22 participants) immediately after a bath. This was a cross‐over trial and we have included only data from the first treatment phase.

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

A similar decrease in mean EASI scores at week 2 from baseline was seen in both groups (scale of 0 to 72, increase represents worsening eczema). Mean decrease in the wet‐application group was 13.3 (SD 7.95) compared to 12.5 (SD 6.04) in the dry‐application group. The MD between groups at end of treatment was 0.80 (95% CI −3.34 to 4.94; P = 0.70; 45 participants) showing no difference.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

In both groups, the mean itch score measured on a numerical rating scale (0 = no itch to 10 = severe itch) decreased at week 1 and 2 compared to baseline. Mean decrease in the wet‐application group was 3.4 (SD 2.65) compared to 2.7 (SD 2.86) in the dry‐application group at week 1. The MD between groups was 0.70 (95% CI −0.91 to 2.31; P = 0.39; 45 participants) showing no difference.

At week 2, mean decrease in the wet‐application group was 4.7 (SD 2.55) compared to 3.5 (SD 2.91) in the dry‐application group. The MD between groups was 1.20 (95% CI −0.40 to 2.80; P = 0.14; 45 participants) showing no difference.

There was an improvement in sleep in both groups reported on a numerical scale (0 = slept well to 3 = slept poorly). At week 1, mean decrease from baseline in the wet‐application group was 0.7 (SD 0.98) compared to 0.6 (SD 0.96) in the dry‐application group. The MD between groups was 0.10 (95% CI −0.47 to 0.67; P = 0.73; 45 participants); showing no difference.

At week 2, mean decrease in the wet‐application group was 0.8 (SD 0.96) compared to 0.6 (SD 0.98) in the dry‐application group. The MD between groups was 0.20 (95% CI −0.37 to 0.77; P = 0.49; 45 participants; showing no difference.

Safety: number of relevant local adverse events (primary outcome)

Three participants in the wet‐application group (22 participants) experienced folliculitis compared to five participants in the dry‐application group (23 participants) over two weeks. There were no cases of skin thinning in either group.

Safety: number of relevant systemic adverse events (secondary outcome)

The trial authors stated, "no patients developed clinical signs of systemic suppression of the hypothalamic pituitary adrenal axis, such as moon faces, fat redistribution, signs or symptoms of glucose intolerance or immunosuppression" measured up to week 2. Mean morning serum cortisol at day 14 was 15 micrograms/dL in the wet‐application group (4 participants) and 12 micrograms/dL for the dry‐application group (6 participants), with one participant having levels of less than 5 micrograms/dL.

Topical corticosteroid applied before emollient versus topical corticosteroid applied after emollient

We included only one trial (Ng 2016) that compared topical corticosteroid applied before emollient (20 participants) with topical corticosteroid applied after emollient (26 participants). This parallel‐group, two‐week trial in children with moderate to severe eczema compared a moderate‐potency steroid applied twice daily, either 15 minutes before or after applying emollient.

Effectiveness: changes in clinician‐reported signs of eczema (primary outcome)

There was a reduction in eczema severity in both groups after two weeks' treatment with topical corticosteroid, measured by EASI, scale of 0 to 72, where an increase represents worsening eczema. In the topical corticosteroid first group, median EASI decreased from 15.5 (IQR 7.3 to 22.0; 20 participants) at baseline to 10.6 (IQR 3.3 to 14.9; 16 participants) at week 1, and 10.4 (IQR 4.9 to 16.1; 12 participants) at week 2. In the emollient‐first group, median EASI decreased from 13.3 (IQR 6.8 to 19.2; 26 participants) at baseline to 7.7 (IQR 3.6 to 13.5; 24 participants) at week 1, and 4.6 (IQR 2.7 to 11.5; 19 participants) at week 2.

Effectiveness: patient‐reported symptoms of eczema (secondary outcome)

Both groups saw some reduction in itch measured on an unspecified scale by week 2. In the topical corticosteroid‐first group, median itch was 6.0 (IQR 5.0 to 8.0; 20 participants) at baseline, 6.0 (IQR 3.0 to 8.0; 17 participants) at week 1, and 4.0 (IQR 2.5 to 7.0; 12 participants) at week 2. In the emollient‐first group, median itch was 6.0 (IQR 5.0 to 8.0; 26 participants) at baseline, 4.0 (IQR 3.0 to 6.0; 23 participants) at week 1, and 4.0 (IQR 3.0 to 6.0; 19 participants) at week 2.

Safety: number of relevant local adverse events (primary outcome)

Local site reactions were reported up to week 2 (see Analysis 11.1). The most frequent event was pruritus, reported in 6 of 20 participants in the topical corticosteroid‐first group compared to four of 26 participants in the topical corticosteroid after group. Overall, there was little difference between groups in local site reactions.

Safety: number of relevant systemic adverse events (secondary outcome)

Systemic adverse events were not reported.

Time between application of emollient and steroid

We did not find any trials that involved the use of this strategy.

Overall effectiveness and safety

Whilst it is important to view the data for each strategy individually, through pairwise comparisons, to answer the specific review questions, there is also merit in considering the overall effectiveness and safety data from this cohort regardless of the strategy for topical corticosteroid use employed. When all trials reporting on IGA are taken together, the number of participants who achieved cleared or marked improvement on IGA was 59% after one to four weeks (Analysis 12.1) and 71% by end of treatment (Analysis 12.2), although it should be noted that there was significant variation between trials in the proportion of participants who achieved cleared or marked improvement, with no obvious reason for the variation. This is coupled with the observation that a minority of trials reported cases of skin thinning, but most reported none. Across all strategies and comparisons, 26 cases of skin thinning were reported in 3574 participants (less than 1%; Analysis 12.3). Sixteen of these were reported when using very potent topical corticosteroid in trials that had not excluded participants with signs of skin atrophy at baseline (Analysis 12.4).

Discussion

A total of 104 trials and 8443 participants were included in this review. These covered a wide range of clinically plausible strategies for using topical corticosteroids in treating eczema, which fell into three broad

which topical corticosteroid to use;how often and how long to use topical corticosteroid for; andhow best to apply the topical corticosteroid.

Summary of main results

The main findings, for which we have drawn up summary of findings tables, address 1. which topical corticosteroid to use, and 2. how often and how long to use topical corticosteroid for.

Which topical corticosteroid to use

See: Table 1, Table 2, Table 3, Table 4.

Our review focused on four comparisons of topical corticosteroid of one potency with another topical corticosteroid of a different potency (moderate versus mild topical corticosteroid, potent versus mild topical corticosteroid, potent versus moderate topical corticosteroid, and very potent versus potent topical corticosteroid) for treating eczema flare‐ups, which reflects clinical practice decision making based on a stepped approach. In mainly moderate to severe eczema, potent and moderately potent topical corticosteroid probably result in an increased number of participants achieving clinician‐reported treatment success compared to mild‐potency topical corticosteroid (moderate‐certainty evidence), with insufficient data to determine whether this applied to people with mild disease. There was also insufficient evidence of a benefit of potent topical corticosteroid compared to moderate‐potency topical corticosteroid (moderate‐certainty evidence). Again, the trials were mainly in moderate to severe eczema but perhaps more representative of the population that may be offered these higher‐potency topical corticosteroids There was insufficient evidence to demonstrate any advantage of very potent over potent topical corticosteroid, with only three small trials included in the meta‐analysis (low‐certainty evidence). These trials usually included more children than adults. The number of reported cases of skin thinning was very low, with a relatively even spread across groups but tending towards more events with increasing potency of topical corticosteroid. Most trials were of short duration so may not detect longer‐term adverse events (low‐certainty evidence for local adverse events, except for the comparison of very potent versus potent topical corticosteroid which we assessed as very low‐certainty.)

In six trials involving 188 participants, 16 participants had levels of cortisol outside of the normal range (very low‐certainty evidence). There were minimal data on whether the levels returned to normal once the topical corticosteroids were stopped, minimal data on clinically relevant adrenal suppression, and no data regarding impact on growth (see: Completeness of outcomes; safety).

How often to apply topical corticosteroid?

See: Table 5; Table 6; and Table 7.

Applying topical corticosteroid twice daily probably does not increase the proportion of participants (adults and children) who achieve clinician‐reported treatment success for treating a flare (1 to 4 weeks) compared to once daily application (moderate‐certainty evidence).This still applied when restricting to trials where the same topical corticosteroid was used in both arms; however, most of those trials were in participants with moderate to severe eczema, using a potent or very potent topical corticosteroid. It also applied in the trials that spanned more than one strategy, comparing higher‐potency, often newer, second‐generation topical corticosteroid applied once a day with lower‐potency topical corticosteroid applied more frequently.

The evidence suggests that frequency of application results in little to no difference between strategies in the risk of developing skin thinning (low‐certainty evidence). The number of reported cases was low, and more than three‐quarters of cases were seen in participants using very potent topical corticosteroid. The evidence addressing whether using topical corticosteroids more than once daily affects cortisol levels is very uncertain and there were no data on clinically relevant effects.

No trials looked at longer‐ versus shorter‐term duration of treatment for induction of remission from a flare.

Weekend, or ‘proactive’ therapy, in which topical corticosteroids are applied twice a week for two consecutive days in between flares, aims to prevent rather than treat eczema flares. Weekend therapy likely results in a large decrease in the likelihood of experiencing a new flare compared to no topical corticosteroid application, with moderate‐certainty evidence. This effect was seen in children and adults and across all eczema severities, although most evidence was in moderate to severe eczema. With regard to safety, no cases of skin thinning, or new cases of abnormal cortisol levels were reported (low‐ or very low‐certainty evidence), but there were no data on clinically relevant adrenal suppression or impact on growth. The trials of weekend therapy were significantly longer in duration (16 weeks to 12 months) than trials identified for other strategies, primarily because of the need to detect the number of new flares rather than treating the existing flare. Whilst these trials may be better designed to detect adverse events that take longer to manifest, such as skin thinning, it should be noted that the data are not necessarily comparable with the other strategy comparisons as the topical corticosteroid use was intermittent (two days per week) rather than daily as is normal for treating a flare.

Other strategies examined

Newer, second‐generation topical corticosteroids, fluticasone propionate and mometasone furoate, are probably more effective than older topical corticosteroids; use of second‐generation topical corticosteroid is approximately two and a half times more likely to result in cleared or marked improvement on IGA compared to older topical corticosteroid in adults and children with moderate or severe eczema when used in the short term for treating a flare. Most trials tested once daily application of the second‐generation topical corticosteroid in line with the marketing strategy compared to twice‐a‐day use of the older topical corticosteroid, supporting the conclusion that these newer topical corticosteroids are probably more effective. However, given many of these trials were industry funded, an independent trial would be beneficial.

Whether a cream or ointment preparation of the topical corticosteroid is used may have little to no effect on clinical signs of eczema, but the evidence is very uncertain with a high degree of imprecision. Similarly, the data from three trials that compared different concentrations of the same topical corticosteroid was not conclusive. We found no evidence comparing the branded versus a generic version of the same topical corticosteroid.

The frequency that topical corticosteroid is applied each week (i.e. every day or less frequently) may have little to no effect on clinical signs of eczema and safety, but the evidence is very uncertain. Substituting an evening application of topical corticosteroid with a topical calcineurin inhibitor may have little to no effect on effectiveness in children with moderate to severe eczema compared to applying topical corticosteroid twice a day, but the evidence is very uncertain from only one very small trial, with no data on skin thinning or adrenal suppression.

Using topical corticosteroid under wet wraps may have little to no effect on investigator‐assessed signs, but the evidence is very uncertain with a high degree of imprecision, and when we addressed the heterogeneity in the limited meta‐analysis, the results favoured topical corticosteroid without wet wraps. Minimal safety data meant that we could not draw firm conclusions, however, skin infections did occur with wet wraps without corresponding events reported in the participants who did not use wet wraps. The time of day that the topical corticosteroid is applied, whether topical corticosteroid is applied to wet or dry skin, or order of application of topical corticosteroid and emollients may have little to no effect on clinician‐reported signs of eczema or implications for safety, but the evidence is very uncertain from only one or two small trials for each comparison. No trials looked at the optimum time to leave between emollient and topical corticosteroid application.

Overall completeness and applicability of evidence

Completeness of participants

Most of the included trials were conducted in high‐income countries and did not report detailed information on the ethnicity of participants; where ethnicity was reported, participants were predominantly white. Eczema in dark skin may present differently to eczema in white skin, for example lichenification is more common in those with darker skin tones and erythema may be underestimated when conducting skin assessments. As a result, it is unclear how the findings of this review inform treatment for people with darker skin tones, as they have been under‐represented in eczema trials to date.

Almost all trials that stated information about location were conducted in outpatient or other hospital settings, and the severity of the eczema in the trial populations does not accurately reflect eczema in the general population. Whilst most people have mild or very mild eczema, trials more commonly included people with moderate and severe eczema. This is particularly relevant for this review as people with moderate or severe eczema are likely to be offered additional treatments over and above topical corticosteroid in practice, making trials of only topical corticosteroid potentially less relevant to this population. That said, the choice of topical corticosteroid for these populations was usually sensible, that is, a more potent topical corticosteroid for more severe eczema.

Most comparisons included trials of adults and children, but due to the overall number of trials per comparison, there were rarely enough trials to conduct meaningful subgroup analyses. Therefore, for many comparisons, it is not possible to clearly determine whether the effect is the same or different in adults and children. This could be significant due to the differences in skin between different age groups. There was also insufficient data with which to compare effectiveness at different anatomical sites.

We excluded some trials because it was not possible to extract the data on only participants with atopic eczema, as these trials had included people with a range of skin diseases or different types of eczema, or both.

Completeness of interventions

Our search included all topical corticosteroids and had no date restrictions. Therefore, it is likely that some of the topical corticosteroids tested are either no longer commonly used or are used in some areas of the world more than others. However, we grouped topical corticosteroids by potency for the purposes of this review, rather than looking at individual topical corticosteroids, which minimises the impact of this.

Owing to the lack of trials that met the inclusion criteria, we did not find sufficient evidence addressing several comparisons of interest. In particular, there were no trials addressing our key comparison of longer‐ compared to shorter‐term duration of use of topical corticosteroids to treat flare‐ups. More generally, of the three broad categories of comparison of 1. which topical corticosteroid to use, 2. how often to apply topical corticosteroids, and 3. how to use the topical corticosteroid, only 10 of 104 trials addressed the third category, how to use the topical corticosteroid. One trial in 45 participants looked at topical corticosteroid applied to wet versus dry skin; one trial in 46 participants looked at whether topical corticosteroid should be applied before emollient versus after emollient; and no trials looked at the optimum time between application of emollient and application of topical corticosteroid. Furthermore, when considering strategies for treatment of a flare (getting control) versus flare‐prevention (keeping control), only one comparison addressed the latter in nine trials of weekend therapy (proactive topical corticosteroid) versus no proactive topical corticosteroid in 1344 participants. We discuss evidence gaps highlighted by this review further under Implications for research.

In this review we included a comparison of concentrations of topical corticosteroid where we included a trial that compared 0.05% fluticasone cream with 0.005% fluticasone ointment (Berth‐Jones 2003). As the vehicle in which the topical corticosteroid is delivered influences the solubility (Oakley 2021), and therefore the effectiveness, then this could be the reason for the difference in concentrations within the formulation. Therefore, the comparison of concentrations within this trial may not be applicable to formulations of the same type.

Completeness of outcomes

Effectiveness

Because there are more than 20 different instruments for measuring signs of eczema (Schmitt 2007), we prespecified a hierarchy of outcome measures. EASI was highest on the list as it is recommended as the core outcome for clinical signs by HOME, however only five trials reported it. IGA was sixth in the list, but it was by far the most reported effectiveness outcome instrument, used in 62 of 104 trials, and therefore most meta‐analyses in this review were conducted using IGA data. As there is no accepted and validated international standard instrument for measuring IGA, to enable synthesis of the data we abstracted the IGA results into a dichotomous outcome of treatment success (cleared or markedly improved) versus not successful (all remaining categories) where possible, reflecting the presentation of these data in most trials. This approach may be less relevant for people with severe or very severe eczema who may be less likely to achieve cleared or markedly improved with only topical corticosteroid.

Patient‐reported outcomes were our secondary effectiveness outcome. Again, we prespecified a hierarchy of preferred outcome measures, with POEM at the top of the list as it has been tested adequately for validity and reliability (Schmitt 2007), and is included in the HOME Core Outcome Set, however none of the included trials reported it. Patient‐reported outcomes that we included were sleep and itch scales, and patient global assessments (15/104). Only a third of trials reported these, and rarely sufficiently to enable meta‐analyses, but where there were data available, they generally supported the conclusions based on clinician‐reported outcomes.

Most of the trials included in this review were short term (1 to 4 weeks' duration) as they were comparing strategies designed to get control of an eczema flare. Trials of weekend (proactive) therapy addressed keeping control of eczema once remission had been achieved. We discuss the need for longer‐term trials with adequate follow‐up under Implications for research.

Safety

Extraction of individual adverse events was restricted to known adverse events of topical corticosteroid, which are well‐established drugs, identified from the Summary of Product Characteristics and prioritised with patient and clinician input. Although reported in this review where finer detail was unavailable, the overall number of adverse events gives no information on the type of adverse event and is not generally helpful in clinical decision making.

Data on individual adverse events were limited and often poor quality. Two of the key adverse events that are of concern to patients and parents are skin thinning and adrenal suppression, however trial authors rarely specified how they had measured skin thinning and there was little information on resolution of adverse events after stopping the topical corticosteroid.

Clinically relevant adrenal suppression was rarely looked for in the included trials; an exception being Kohn 2016, that compared topical corticosteroid application to wet versus dry skin. Some trials did measure and report cortisol levels, but the certainty of this evidence was consistently very low. Trials used different methods for measuring cortisol, often with little or no interpretation regarding whether the levels were abnormal and without specifying the reference ranges used. Some trials only tested a small subset of participants and reporting was often poor, lacking key numerical data. Furthermore, there were minimal data on whether this biochemical measurement returned to normal levels when topical corticosteroid was stopped, which would have provided an indication of the clinical relevance of such measurements. Additionally, the relatively small size of most trials (median 44.5 participants; range 3 to 409) means they are unlikely to be able to detect all but the most common adverse events. As a result, we are unable to draw conclusions from these data.

As many of the included trials were short term, of just a few weeks’ duration with no post‐treatment follow‐up, this limited the ability to detect adverse events that take months or years to develop, such as skin thinning or hypopigmentation. This can lead to interpretation as evidence of no effect when in fact it could be no evidence of an effect. These short trials are a snapshot of a patient’s eczema journey involving many years of treatment, which further hampers the ability to detect potential adverse events. Trials of weekend (proactive) therapy provide some data on prolonged use of topical corticosteroid over several months albeit with less frequent use than the current standard daily application for the management of flares.

We excluded one large, notable trial (PETITE) from this review because it did not compare different strategies of using topical corticosteroid (Sigurgeirsson 2015). The PETITE trial randomised 2418 children to receive topical corticosteroid (mild/moderate) or topical calcineurin inhibitors, used as required, and followed them for five years. This trial reports that clinical skin thinning occurred in one of 1213 participants (0.08%) who used mild to moderate topical corticosteroid over five years. We mention the trial here for context as it is the only large trial of normal topical corticosteroid use over a long period.

Quality of the evidence

We GRADE assessed almost all clinician‐reported effectiveness outcomes as moderate, with only one judged very low. The reason for downgrading the effectiveness outcomes was due to issues identified by the risk of bias assessment and in the comparison classed as low, imprecision. Only half of the comparisons from the summary of findings table reported complete numerical data for the most reported patient‐reported outcome; patient global assessment. Of those that did, one provided moderate‐quality evidence, one low, and one very low. The reason for downgrading the data obtained from this analysis was again issues from the risk of bias assessment, and in the trials assessed as low, unexplained heterogeneity. In the comparison classed as very low, small numbers of events and participants meant we downgraded the comparison twice for this outcome in addition to the risk of bias concerns.

We judged all but one comparison low with regards to the data concerning skin thinning. This was again due to issues highlighted by the risk of bias assessment and imprecision. The comparison in which we classed the skin thinning data as very low was downgraded twice for imprecision due to low numbers of events and participants.

In all assessments of the evidence associated with abnormal cortisol assessment, we judged the certainty of the evidence as very low. This was due to risk of bias issues and low numbers of events and participants. One comparison also demonstrated inconsistency.

Where we sought further information from authors relating to risk of bias assessments, our requests for further data did not always get a response (see Table 10). In many cases, this is likely owing to the age of the included trials.

We did not downgrade any GRADE assessments due to publication bias. However, only two analyses that included assessment of short‐term IGA from the potent versus moderate and twice or more versus once daily topical corticosteroid comparisons, included enough trials to allow the generation of valid funnel plots. Both showed no clear asymmetry (Figure 5 relating to Analysis 3.1; Figure 6 relating to Analysis 7.1).

Potential biases in the review process

The categorisation of topical corticosteroid potency is contentious. There is no one source of potency categorisation, and there are discrepancies between the different sources. Therefore, to ensure transparency and minimise bias, we developed a hierarchy of sources to assign potency to each topical corticosteroid (Table 9). We most frequently determined potencies using the British National Formulary 2018 and WHO 1997. If we could not establish potency using these sources, we reviewed regional guidelines and the wider scientific literature, and consulted regional experts until we could reach a decision. Although these sources are the most appropriate choice for this review, the evidence behind each potency classification is not always clear and manufacturers do not always state the potency of products in the Summary of Product characteristics.

Although the search included the terms for topical corticosteroids, it also included a comprehensive list of generic topical corticosteroid names. It is possible that this list was incomplete and therefore some trials missed from the search if they had not also included the term topical corticosteroids.

We have presented odds ratios (OR) rather than risk ratios (RR) for dichotomous analyses because for some comparisons a high proportion of the trials (up to 50% in some cases) had a within‐participant design, and presenting a RR is inappropriate when the generic inverse variance method (GIV) with Becker‐Balagtas correction is used to incorporate these within‐participant trials. To ensure consistency across comparisons, we presented all meta‐analyses as OR including those with no within‐participant trials. The exception to this is the comparison of weekend (proactive) therapy versus no topical corticosteroid, where meta‐analyses of dichotomous data were reported as RR to be comparable to a previous systematic review (Schmitt 2011).

It was not always clear how the total number of participants in the analyses had been arrived at in some trials and this was compounded by the design of trials in which participants withdrew when the flare was controlled. Where the number of participants at later time points was unclear, we have assumed the number randomised, or the sample size reported for the previous visit if available, which may have resulted in overestimation in some instances.

We dichotomised the IGA data into cleared or almost cleared versus those who did less well. Some trials used an IGA with different response options, so we had to make a judgement regarding which categories best corresponded to cleared or marked improvement in some cases.

Where a trial stated in the methods that they looked for adverse events, but did not report data in the results, we assumed there were no cases. This ought to be a reasonable assumption, as trials ought to be more likely to report adverse events where they occur, however, we acknowledge this may be inaccurate. Furthermore, it was not always clear in the trial reports where adverse event data were reported as number of participants or number of events; in these instances, we have assumed number of participants as a conservative approach to over‐estimate, rather than potentially underestimate, number of adverse events. However, where trials reported on multiple adverse events, and especially when skin thinning was reported separately to signs of skin thinning, for example, telangiectasia, such numbers were not combined to avoid double counting of individuals. Signs of skin thinning have not been included in summary of findings tables; however, they are reported in full in a separate sub‐table under the skin thinning tables (e.g. Analysis 7.10).

We attempted to conduct a comprehensive search for trials, but the fact that 24 trials have not yet been incorporated may be a source of potential bias.

Agreements and disagreements with other studies or reviews

The recommendations for the use of topical corticosteroids related to the main comparisons reported within this review, (results reported in the summary of findings tables), were extracted from four international guidelines for the management of atopic dermatitis (from the UK, USA, Europe and Japan). The recommendations are reported in Table 16  with a summary of the results of the review.

All but one of the guidelines consulted recommended a specific potency or potencies for different severities of atopic dermatitis, however the potency or potencies that were recommended for a particular severity varied between guidelines. This is likely to be related to the different severity and potency classifications used in different countries. Most guidelines suggested topical corticosteroids could be applied once or twice daily, but three out of the four guidelines mentioned twice daily use first and then said once daily use "can" be used. All of the guidelines recommended weekend (proactive) use of topical corticosteroid, however the level of support for this approach varied between the regions. This may have been related to the age of the different guidelines. Most of the guidelines, (3 out of 4), suggested patients should be monitored for cutaneous effects. With regards to systemic effects, most guidelines did not specifically mention the need for monitoring, but usually included either restrictions on the use of certain potencies in some circumstances, or warnings about the need to consider the potential for adverse effects when using certain potencies.

We used the Centre of Evidence Based Dermatology map and an overview of systematic reviews (Axon 2021), to identify key literature. Below, the results of this review are compared to UK guidelines and relevant systematic

UK National Institute for Health and Care Excellence (NICE)

Key areas where this review supports NICE guidance (NICE 2007).

NICE says do not use very potent preparations in children without specialist dermatological advice. Most cases of skin thinning collated into this review were in participants using very potent steroids. We assessed the evidence found within this review relating to the rates of skin thinning using GRADE as low or very low certainty.NICE says start with mild steroids for those with mild eczema. Within the potent versus mild topical corticosteroid comparison, there was no difference between mild and potent topical corticosteroid in participants with mild to moderate eczema, suggesting that mild steroids may work well enough for this group, however this only considered 43 participants from two trials and the confidence interval was wide compared to the data in moderate to severe eczema, which favoured potent topical corticosteroid. Furthermore, as there were more reports of skin thinning in more potent steroids, the trade‐off of more effectiveness from higher potency does not seem necessary for this group unless it fails to control the flare. The evidence for potency in relation to specific disease severities was not GRADE‐assessed independently from the overall analysis of potency.NICE says healthcare professionals should discuss risks and benefits, emphasising that the benefits outweigh possible harms when topical corticosteroid are applied correctly. Most participants had a good response to topical corticosteroids, these results were taken from within trials usually GRADE‐assessed to be of moderate certainty. Rates of adverse events such as skin thinning were generally very low, though we GRADE‐assessed this evidence as low or very low certainty.NICE says prescribe according to lowest acquisition cost. We did not find any data that compared generic and branded topical corticosteroids.NICE says healthcare professionals should consider treating problem areas of atopic eczema with topical corticosteroids for two consecutive days per week to prevent flares, instead of treating flares as they arise, in children with frequent flares (2 or 3 per month) once the eczema has been controlled. This strategy should be reviewed within three months to six months to assess effectiveness. This review supports weekend (proactive) therapy for the prevention of eczema flares, including in children, however more trials are needed to verify for how long this should be continued (effectiveness evidence for weekend (proactive) therapy GRADE‐assessed as moderate certainty).This review confirms the research gap identified by NICE regarding a lack of good, long‐term data on topical corticosteroid safety. For example, we GRADE‐assessed the safety data reported for the main comparisons reported in the summary of findings tables as low or very low certainty.

Key differences with NICE guidance.

NICE says use once or twice a day. This review suggests there is no evidence of additional effectiveness of application of potent topical corticosteroids once a day over twice a day (we GRADE‐assessed the evidence as moderate certainty). For mild or moderate topical corticosteroids there is a lack of evidence regarding once‐ or twice daily application.NICE says there is limited evidence on strategies to prevent flares. This review provides moderate‐certainty evidence for use of weekend (proactive) therapy.This review suggests that newer, second‐generation topical corticosteroids are probably more effective than older topical corticosteroids; this is not included in NICE guidance. We did not GRADE‐assess the evidence within this analysis as it was not one of the main comparisons reported in the summary of findings tables.

We found limited or no evidence to support some of the recommendations in NICE.

NICE says occlusion strategies should not be used as first‐line treatment in children, should only be initiated by a healthcare professional trained in their use, and should only be used for 7 to 14 days without specialist dermatological advice.NICE says do not use potent topical corticosteroids in children under 12 months without specialist dermatological supervision.NICE says to start treatment of moderate eczema with moderate‐potency topical corticosteroid and severe eczema with potent topical corticosteroid. Whilst this review supports the notion that stronger topical corticosteroids probably have increased effectiveness, there was insufficient data in participants with mild to moderate eczema to fully support this stepped approach.NICE says, in children over 12 months, to use potent topical corticosteroids for as short a time as possible and in any case for no longer than 14 days.NICE says to use mild potency for the face and neck, except for short‐term use of moderate‐potency topical corticosteroids for severe flares, and to use moderate or potent preparations for short periods only in the axillae and groin.

Scottish Intercollegiate Guidelines Network (SIGN)

Key areas where this review supports SIGN guidance (SIGN 2011):

SIGN recommends once daily topical corticosteroid use. This review clarifies that the evidence base suggests this is most appropriate for potent and very potent topical corticosteroid (GRADE‐assessed as moderate‐certainty evidence) being used to treat moderate to severe eczema. For mild or moderate  topical corticosteroid there is a lack of evidence regarding once or twice daily application.SIGN says there is a lack of evidence on which to base the order of topical corticosteroid and emollient application, maximum duration of continuous use, the frequency with which strategies can be repeated, and recommendations for growth monitoring. This review confirms this paucity.SIGN says that the short‐term use of topical corticosteroid is not associated with observable skin thinning. The rates of skin thinning were low across this review, though we GRADE‐assessed the body of evidence with regards to skin thinning as low or very low certainty.

Key differences with SIGN:

SIGN suggests no comprehensive evidence was identified comparing topical corticosteroid with each other in terms of effectiveness. This review suggests that newer, second‐generation topical corticosteroids are probably more effective than older topical corticosteroids, use of stronger‐potency topical corticosteroid according to our classification (Table 9) is probably more effective than weaker topical corticosteroid, and confirms the lack of evidence comparing generic versus branded topical corticosteroid. We did not GRADE‐assess the evidence within this analysis as it was not one of the main comparisons reported in the summary of findings tables.SIGN says that three RCTs suggest that adding twice‐weekly topical corticosteroid application to emollient‐based maintenance therapy following stabilisation of eczema reduces relapse rates. This review updates this evidence, informed by eight trials, GRADE assessed as moderate certainty.

As with NICE, we found limited or no evidence to support some of the recommendations in SIGN, including the choice of topical corticosteroid potency being tailored to the age of the patient, the body region being treated, and the degree to which the skin is inflamed.

Strategy‐focused reviews

Daily frequency

This review accords with previous systematic reviews (Green 2004; Green 2005), in concluding that there is probably (evidence GRADE‐assessed as moderate certainty) no benefit of topical corticosteroid application more than once daily, building on that initial work with the addition of data from two newer RCTs (Del Rosso 2009; Schlessinger 2006), and several older and foreign language publications (Amerio 1998; Harder 1983; Lebwohl 1999; Nolting 1991; Rafanelli 1993; Rampini 1992a; Ryu 1997). Green and colleagues did include data from an unpublished trial, which could not be obtained for this review (GSK 1995). However, given that the conclusion of this review agrees with Green 2004, it is unlikely to change should GSK 1995 be included in future.

Weekend therapy

The results presented in this review confirm that weekend (proactive) therapy is probably (evidence GRADE‐assessed as moderate certainty) of benefit in preventing flares and update the findings of a previous systematic review (Schmitt 2011), with the addition of four further RCTs, two of which we were able to pool.

Wet wrap

Our review included the same six trials of wet wrap therapy as a previous review that also showed there may be little or no benefit of wet wrap (not GRADE‐assessed), and cases of skin infection with wet wraps (González‐López 2017). However, the effectiveness results in this review are numerically different because of the method used to include within‐participant trials and adjust for baseline differences between groups where possible.

Safety‐focused reviews

Skin thinning

Issues highlighted by this review regarding certainty of skin thinning data (GRADE‐assessed as low or very low certainty) and the need for long‐term clinical trials of treatment regimens involving topical corticosteroid have been raised previously (Barnes 2015).

Adrenal suppression

The included trials rarely reported clinically relevant adrenal suppression. In those that reported biochemical markers, the certainty of the evidence was very low, often in a small subset of participants, with poor reporting, and missing numerical data. A systematic review that included nine trials of children, one RCT included in this review (Lucky 1997), and eight observational trials (371 participants), pooled the number of participants with biochemical markers of adrenal suppression. It found that the proportion of cases in those using low‐ to moderate‐potency topical corticosteroid in the short term was 2.7% (95% CI 1.47 to 4.89), however there were no cases showing any clinical signs of adrenal suppression (Davallow Ghajar 2019), which accords with this review. Another meta‐analysis by the same authors looking at topical corticosteroids of any potency, therefore also including Schlessinger 2006, reported that risk of adrenal suppression increased with increasing topical corticosteroid potency, but concluded that monitoring was unnecessary even with highest potency unless clinical symptoms were present (Wood Heickman 2018).

Topical corticosteroid withdrawal

None of the RCTs included in this review reported outcome data related to topical corticosteroid withdrawal, therefore this review does not advance the topic from previous systematic reviews of observational data (Hwang 2021; Juhász 2017; Li 2017).

Authors' conclusions

Implications for practiceThe purpose of this review was not to prioritise one strategy over another, but rather to summarise all the available evidence on the relative safety and effectiveness of different ways of using topical corticosteroids. Most participants had a good response to topical corticosteroids, regardless of the type of topical corticosteroid used and when or how it was applied. This overall effectiveness should be considered alongside the observation that rates of adverse events associated with the use of topical corticosteroids were generally low and associated with potent or very potent topical corticosteroids. Although the trials were usually short term, of just a few weeks’ duration, many will have included people with established eczema who may have been using topical corticosteroids for several months or years prior to entry to the trial.The finding that once daily application of potent topical corticosteroid appears to be probably as effective as applying topical corticosteroids twice or more per day is significant for patients and parents as the application of topical treatments for eczema can be burdensome. Clear advice that only once a day is needed may help with adherence. Applying topical corticosteroid just once a day may also reduce costs to patients and caregivers and the state. There is currently insufficient evidence to confirm if this finding is relevant for mild topical corticosteroid use and for participants with mild‐ to moderate‐severity eczema.The data in this review supports the concept of reserving very potent topical corticosteroids for those with the most severe eczema, as skin thinning was more frequent with use of very potent topical corticosteroids, and the evidence for superiority over potent preparations was lacking. Additionally, the relatively good safety profile of moderate and potent topical corticosteroids and the finding that they are probably more effective than mild topical corticosteroids for people with moderate to severe disease confirms the use of the more potent topical corticosteroids for these patients. However, further trials are needed in mild eczema, along with trials of how long the topical corticosteroid should be used to treat a flare before any changes to current guidelines can be made. It is possible that a shorter duration of a higher‐potency topical corticosteroid is as safe and effective as a lower‐potency topical corticosteroid used for longer to control a flare and may be less burdensome to people with eczema; one trial compared a potent topical corticosteroid for three days per week with mild topical corticosteroid for seven days (Thomas 2002).This review confirmed previous findings that weekend (proactive) therapy, in which topical corticosteroids are applied twice a week on consecutive days, is probably effective in preventing flares, compared to no topical corticosteroid/reactive application. However, in current clinical practice, this strategy is generally recommended by specialists and considered appropriate only for people who experience regular flares. The data here, albeit only from two trials, show that this strategy may also be effective and safe for people with milder disease and may result in wider adoption into primary care. It is also important to note that trials that investigated prevention of flares would typically treat participants with an intense (e.g. once a day for 2 weeks) period of topical corticosteroid to get the eczema under control. It is unclear whether proactive therapy prevents flares without first settling the eczema down, that is, a 'get control and then keep control' approach.The newer, second‐generation topical corticosteroid (mometasone furoate and fluticasone propionate, which are now also available as generic preparations) were more effective than older topical corticosteroids, and the very low rates of skin thinning were similar across the two. There was a significant emphasis on safety in this review driven by the notion that despite being effective, associated adverse events are one of the key barriers to use of topical corticosteroids. Skin thinning is a key issue for adults with eczema and for parents of children with eczema, both skin thinning and concerns about growth are important. Although the safety data were often poorly reported, making it difficult to comment on the relative safety of different strategies for use of topical corticosteroids, taken together as an overall body of evidence, the risk of developing important adverse events like skin thinning, and affecting adrenal suppression, appears to be low. This may help clinicians in discussing topical corticosteroids as a key treatment for eczema and may help patients overcome concerns regarding their use. The observation that the low rates of skin thinning appeared to be largely associated with potent or very potent topical corticosteroids should also be considered when prescribing topical corticosteroids. Due to a lack of evidence, it is not possible to comment on whether any adverse events like skin thinning are reversible once the topical corticosteroid treatment is stopped.The overall data on effectiveness showing that, regardless of which topical corticosteroid is applied or how, it appears to be a very effective treatment suggests that the most important aspect of topical corticosteroid use is simply getting it on the eczematous skin, and that more specific guidance is perhaps less important. Eczema is an inflammatory skin condition that requires anti‐inflammatory treatment such as topical corticosteroids. Emollients are used alongside topical corticosteroids for treating the dry skin associated with eczema (see: Van Zuuren 2017), but they are not an anti‐inflammatory treatment per se. That said, patients report that the lack of consistent advice on how to use topical corticosteroids is one of the factors that affects adherence to treatment. Some areas of the body, such as the face or genital areas, are more sensitive than others, and may require different treatments from the rest of the body, for example, a mild‐ or moderate‐potency topical corticosteroid on the face and a potent topical corticosteroid for the body. Written action plans may be helpful to provide clearer instructions on what to use, for how long and on which body site (Waldecker 2018).

Implications for researchThere is a clear need for good‐quality, long‐term safety trials. The PETITE trial (Sigurgeirsson 2015), although out of scope for this review, provides reassurance over the safety of topical corticosteroids over five years. However, it is only one trial and more, similar‐quality evidence is needed to fully address important questions in eczema research. An overview of systematic reviews (Axon 2021), and a scoping of the literature for a planned review of long‐term safety including observational and randomised trials found a lack of observational trials meeting these criteria. Future RCTs should include longer follow‐up to increase the body of longer‐term safety evidence. A relatively large (750 participants) ongoing parallel‐group trial of proactive use of a second‐generation topical corticosteroid versus reactive therapy to prevent occurrence and severity of atopic dermatitis leading to development of food allergy is expected to measure effectiveness at 36 months (NCT03742414), however it is unclear what other safety outcomes will be measured. An independent trial to confirm whether second‐generation topical corticosteroids are superior to older topical corticosteroids is also needed given the high proportion of industry‐funded trials included in this review.Adverse events also need to be much better measured and reported. How clinically significant skin thinning is measured should be standardised so data across trials can be properly compared. Clinically relevant adverse events relating to hypothalamic pituitary axis suppression, rather than just cortisol levels, should also be measured and reported. Trials need to investigate and report whether adverse events are reversible as this would help understand and manage risks. Most of the trials included in this review were in outpatient or other hospital settings with people with moderate and severe eczema, yet most people with eczema have mild or very mild disease. For example, whilst this review found that once daily application of potent topical corticosteroids in moderate to severe eczema is probably as effective as twice daily, this finding cannot be generalised to milder topical corticosteroids and milder‐severity eczema. There is a need for further research in people with milder disease treated in the community, especially as they are more likely to achieve treatment success with optimal topical corticosteroids and without the need for additional systemic therapies. An ongoing pragmatic randomised controlled open‐label trial of second‐generation potent topical corticosteroids versus mild topical corticosteroids in children in primary care settings may add useful insight and will measure effectiveness at up to 24 weeks (Van Halewijn 2018; within The Rotterdam Eczema Study). This review has also highlighted the need for further research into the effectiveness and safety of topical corticosteroids when applied to the skin of participants of different age groups and when topical corticosteroid is applied to skin at different anatomical sites. There is also an urgent need to explore if and how the effectiveness and safety of topical corticosteroids differs in participants with darker skin tones. Future trials should aim to include more diverse patient populations and for interventions to be tested in a variety of settings and healthcare systems.Research is needed to determine how long topical corticosteroids should be used to induce remission when treating a flare as we found no evidence on this important question (one exceptionally small pseudorandomised trial did not meet the inclusion criteria for this review; JPRN‐UMIN000010299; 4 participants). This should be combined with assessing the potential for higher‐potency topical corticosteroids to be used for a shorter period. Another unanswered question relating to maintenance treatment, such as weekend (proactive) therapy, is when to stop and switch to reactive (as needed) treatment when control has been good for a few months with proactive therapy.Other comparisons that had minimal evidence for their effectiveness might also be further researched. The third group of strategies, under 'How to use the topical corticosteroid', are particularly important to both patients and healthcare professionals. Some individuals may be liberated by the idea that ‘you can choose’ how to use topical corticosteroid, however others are likely to be disconcerted without evidence to guide their choices of whether to apply emollient or topical corticosteroid first, or how long to leave between application of emollient and topical corticosteroid.Additional evidence comparing potent topical corticosteroid application under wet wrap to potent topical corticosteroid alone is expected from an ongoing trial (EUCTR2005‐003806‐27‐GB). A within‐participant trial comparing two different concentrations of hydrocortisone in addition to a second‐generation potent topical corticosteroid is also ongoing (NCT04615962). However, we found no further trials that would address these under‐researched comparisons.Investigator global assessment (IGA) was the most reported effectiveness outcome and most meta‐analyses in this review were conducted using IGA data. There is a need for further trials using outcome measures recommended by the Harmonising Outcome Measures for Eczema (HOME) initiative. It is encouraging to see ongoing trials proposing to use outcomes such as the Patient‐Oriented Eczema Measure (POEM) and Eczema Area and Severity Index (EASI; NCT03742414; NCT04615962; Van Halewijn 2018). Recap of Atopic Eczema (RECAP) and Atopic Dermatitis Control Test (ADCT) have also recently been included under the core outcome of long‐term control.

History

Protocol first Issue 6, 2019