Strategies for using topical corticosteroids in children and adults with eczema New

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 corticosteroids: 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.

Author(s)

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

Plain language summary

What is the best way to use topical corticosteroids to treat people with eczema? 

Key messages 

‐ Generally, stronger topical corticosteroids (steroid cream applied to the skin) are probably more effective than weaker preparations. Strong steroid cream applied once daily is probably as good as twice daily, and using steroid cream for two consecutive days weekly probably prevents eczema flare‐ups.

‐ About a third of studies looked for skin thinning, but cases were very low. This made it difficult to judge differences between strategies, although there were more cases with stronger steroid cream.

‐ We need better‐quality research on unwanted effects, over longer timeframes, but intermittent use of steroid cream probably causes fewer unwanted effects.

What is eczema and how is it treated? 

Eczema is a common, long‐lasting condition that results in inflamed, dry, itchy patches of skin and its severity varies; it is incurable currently, so treatment aims to control symptoms (inflammation and itching). The first choice of treatment is emollients (moisturisers) combined with treatment to reduce inflammation, often steroid cream.

What did we want to find out? 

Steroid creams can be used in different ways to treat eczema, and people often feel confused about which ones to use, and how often and how best to use them. We wanted to investigate the effectiveness of different ways (strategies) of using steroid cream and whether they cause unwanted effects.

What did we do? 

We summarised evidence from studies that tested different ways of using steroid cream in adults and children. We assessed treatment strategies based on changes in eczema severity assessed by doctors/researchers or participants, and unwanted effects, such as skin thinning (the skin may bruise and tear more easily). We compared and summarised their results, and rated our confidence in the evidence, based on factors such as trial methods and sizes.

What did we find? 

Most studies were conducted in high‐income countries, likely in hospitals, and were short term (range 1 to 6 weeks); studies that assessed prevention of eczema flares lasted longer, but under 6 months. Participant age varied; 43 studies included children only. Eczema was moderate or severe in 51 studies, mild to moderate in 16 studies, mild to severe in 3 studies, and 34 studies did not report severity. Approximately half of the studies were funded by companies that produced the steroid cream or had links to industry; 44 did not report their funding source.

We included 104 studies with 8443 people.

‐ Stronger versus weaker steroid cream (63 studies).  We combined data from 31 studies and 2018 people. The chances of achieving cleared or marked improvement, assessed by a healthcare practitioner, were probably increased with use of stronger‐potency steroid cream. For 1000 people treated, it is likely that 340 to 390 would be clear or almost clear using mild‐potency steroid cream; 460 to 520 would be clear or almost clear using moderate‐potency steroid cream; and 530 to 710 would be clear or almost clear using potent steroid cream.

‐ Twice daily versus once daily steroid cream application (25 studies).  We combined data from 15 studies with 1821 people. Applying strong steroid cream once daily is probably as effective as twice daily application. Studies did not report unwanted effects well, and we are uncertain about some results. Twenty‐two studies (2266 people) reported skin thinning. They identified 26 possible cases, 16 with very strong steroid cream, 6 with strong, 2 with moderate, and 2 with mild steroid cream.

‐ Longer versus shorter steroid cream duration (0 studies) 

‐ Twice‐weekly application (using steroid cream for two consecutive days per week) to prevent flare‐ups versus no application (9 studies).  We combined data from 7 studies (1149 people). Twice weekly steroid cream probably decreases the chance of eczema flare‐ups. For 1000 people using flare‐control creams twice weekly, we would expect approximately 248 to have one or more new flare‐up compared to 576 people not using this strategy. No cases of skin thinning were identified in 7 flare‐up prevention studies (1050 people).

‐ Other comparisons.  We also looked at newer versus older steroid cream preparations, cream versus ointment, steroid cream used with wet wrap, daily versus less frequent application, different strengths of the same steroid cream, time of day applied, steroid cream alternating with topical calcineurin inhibitors (e.g. Protopic and Elidel) versus steroid cream alone, application to wet versus dry skin, and before versus after emollients. No studies compared branded versus generic steroid cream or time between application of emollient and steroid cream.

What are the limitations of the evidence? 

Overall, we are moderately confident about the results on the effectiveness of steroid creams to treat eczema, but we have little confidence in results on unwanted effects, because studies were small and did not always use the most reliable methods.

How up to date is this evidence? 

The evidence is up to date to January 2021.

Author(s)

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

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

The 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 research 

There 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.

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