Workstream 2 addresses objective 2 of the ECO programme: to update and combine existing evidence around the safety and effectiveness of TCSs and develop knowledge tools for patients and healthcare professionals.
This section includes four studies.
- Workstream 2.1: an umbrella review of existing systematic reviews of studies using topical steroids for eczema.
- Workstream 2.2: a Cochrane systematic review of the safety and effectiveness of different strategies for using TCSs.
- Workstream 2.3: a systematic review of the long-term safety of TCSs in eczema.
- Workstream 2.4: creation of knowledge tools to support patients and healthcare professionals.
Workstream 2.1: an umbrella review of existing systematic reviews of studies using topical steroids for eczema
This work has been published:
https://doi.org/10.1136/bmjopen-2020-046476.36 PROSPERO registration number CRD42018079409.
Aims
- To summarise what is known about the safety of using TCSs from published systematic reviews.
- To inform the development of the ECO intervention (workstream 3).
Methods
Design
A systematic review of published systematic reviews. The last search date was 2 March 2021. Reviews were included if they assessed the safety of TCSs in atopic eczema and searched > 1 database using a reproducible search strategy. Review quality was assessed using version 2 of ‘A MeaSurement Tool to Assess systematic Reviews’ (AMSTAR 2 tool).37
The intervention of interest was any TCS strategy used to treat eczema. The comparisons of interest were any other TCS, the same TCS used in a different way, another topical anti-inflammatory treatment, vehicle, no treatment, or a combination of any of these. Comparisons with non-topical treatments were excluded as we were interested in clinical practice decisions regarding alternatives to TCSs.
Safety outcomes were extracted where reported in the reviews on immediate cutaneous adverse events (e.g. burning sensation/stinging), other cutaneous adverse events (e.g. skin thinning, telangiectasia, skin infections, folliculitis), systemic adverse events (e.g. effects on the endocrine system, impact on growth) and rebound symptoms/steroid withdrawal.
Results
This review included 38 systematic reviews (35 in English, 2 in Chinese and 1 in German). The reviews included 106 studies (77 RCTs and 29 observational studies).
Key findings
- We found no evidence that TCSs cause harm when used intermittently ‘as required’ to treatment eczema flares or as ‘weekend therapy’ to prevent flares.
- Adverse events of greatest concern to patients and clinicians, such as skin thinning, were uncommon with short-term use of TCSs. However, high-quality evidence was limited.
- Resolution of adverse events was rarely reported. For adverse events such as skin thinning or biochemical signs of adrenal suppression, it is important to know if the effect is transient and if levels return to normal once the TCS is stopped.
- Treatment decisions are a balance of benefits and harms. See workstream 2.2 for a Cochrane review of the effectiveness and safety of different strategies for using TCSs.
Conclusion
Conclusions were limited by the content of the included reviews and safety was frequently reported in less detail than effectiveness. It is not clear whether this is because the original trials did not report adverse events in sufficient detail or whether the review authors did not include all the available safety data, perhaps only focusing on a restricted group of adverse events.
Most of the included reviews were rated low or critically low quality using AMSTAR 2.37 Where the quality of evidence assessments [e.g. Grading of Recommendations Assessment, Development and Evaluation (GRADE)] were reported in the reviews, most individual studies included in the reviews indicated a high or unclear risk in at least one domain. Many RCTs did not include follow-up beyond 2–4 weeks of treatment and therefore data on long-term safety are limited. Although short-term TCS use reflects an appropriate treatment duration for treating an individual flare, it does not reflect the chronic nature of eczema and the need for TCS use over the long term. Longer-term prospect observational studies are better placed to explore the longer-term safety of TCS and should be designed with years rather than months of follow-up (see workstream 2.3 for an overview of long-term studies).
Impact on intervention development
This review informed development of the ECO intervention prior to testing in the online RCTs (workstream 4).
Workstream 2.2: a Cochrane systematic review of the safety and effectiveness of different strategies for using topical corticosteroids
This work has been published:
https://doi.org/10.1002/14651858.CD013356.pub2.38
Aim
- To summarise what is known about the safety and effectiveness of different strategies for using TCSs.
Methods
This Cochrane systematic review of RCTs evaluated different strategies for using TCSs (last searched January 2021). Trials including people with a diagnosis of eczema of any severity were included. The interventions were any TCS used in a trial where a clinically relevant strategy of TCS use was compared to another (Figure 3).
FIGURE 3 Summary of strategies for using TCSs included in the review. (Figure not reproduced here; see the original article.)
Effectiveness and safety outcomes were assessed using the international Harmonizing Outcome Measures for Eczema (HOME) initiative’s recommended core outcome domains of clinician-reported signs and patient-reported symptoms of eczema.39 The safety outcomes were clinically relevant local (e.g. skin thinning) and systemic adverse events (e.g. adrenal suppression). Outcomes were GRADE assessed for quality.
Results
The review included 104 RCTs in children (n = 43), adults (n = 16), both (n = 17), or unspecified ages (n = 28), with a total of 8443 participants (range 3–409 per trial). Most were parallel-group (n = 63) or within-participant studies (n = 39) conducted in high-income countries (n = 81) and were largely conducted in outpatient or other hospital settings. See Appendix 4, Table 6 for table of included studies.
Eighteen treatment strategies were evaluated in the review. The pre-specified strategies of main interest were
- different potencies of TCSs;
- frequency of applications of TCSs;
- duration of use for treatment of a flare;
- weekend (proactive) therapy for the prevention of flares.
Conclusions were based largely on the number of cleared or marked improvements in Investigator Global Assessments at 1–5 weeks in flare treatment trials, and the number of relapses by 16–20 weeks in weekend (proactive) therapy trials.
Key findings
- To treat flares of moderate to severe eczema, there is evidence that moderate and potent TCSs are better than mild TCSs; and once-daily potent TCS is as effective as twice daily, but the optimal duration of TCS use is unknown.
- There is evidence that ‘weekend therapy’ (prophylactic use of TCS 2 consecutive days every week) with potent TCSs may prevent flares of moderate to severe eczema.
- Adverse events were infrequent (e.g. skin thinning in < 1%), but reporting was poor.
- Evidence for other strategies was lacking.
Details of the key findings are summarised in Report Supplementary Material 1.
Conclusions
Treatment regimens could be simplified by recommending the use of TCS once per day.
While these findings provide some reassurance that using TCSs intermittently to treat eczema flares is safe, there were several strategies of interest that had not been addressed in adequately powered clinical trials. Outcome measurement and reporting were suboptimal in many of the included trials, with a lack of HOME core outcome set outcomes. Where safety outcomes were reported, they often lacked detail, were inconsistently reported and had insufficient duration of follow-up.
A further challenge to interpretation is that the classification of potency is viewed differently worldwide, making comparisons of TCS potency as used in the reported trials more difficult.40
There is a growing interest in TCS withdrawal within people with eczema, but no trials specifically addressed this.
Impact on the Eczema Care Online intervention
This review informed the final content of the ECO intervention (workstream 3) and the development of the clinical practice knowledge tool (workstream 2.4).
Workstream 2.3: a systematic review of the long-term safety of topical corticosteroids in eczema
This review is published.
https://doi.org/10.1002/ski2.268.41 PROSPERO registration number CRD42021286413.
Aim
- To conduct a systematic review of adverse effects associated with the long-term use of TCS for eczema.
Methods
This was a systematic review of RCTs, cohort studies and case-control studies that reported adverse effects of TCSs when used in patients with eczema (search date December 2021). Included studies had > 1 year of follow-up, a minimum cohort size of 50 participants, or a minimum of 50 per arm for RCTs. Risk of bias (ROB) was assessed using Cochrane ROB2, Cochrane Risk Of Bias In Non-randomized Studies – of Interventions (ROBINS-I) and Newcastle Ottawa Scales (as appropriate). Evidence was GRADE-assessed. Results were presented narratively.
Results
Two RCTs (n = 2570, including 1288 receiving TCS), two cohort studies (n = 148) and three case-control studies (cases n = 10,322, controls n = 12,201) were identified. The studies reported on local adverse effects (skin thinning), and systemic adverse effects (type 2 diabetes, lymphoma, growth abnormalities, bone mineral density reduction, signs of adrenal insufficiency, non-skin infections, impaired vaccine response and other non-lymphoma malignancies). No long-term studies concerning topical steroid withdrawal or eye problems were identified.
Key findings
- Overall, the limited body of evidence provides some reassurance that TCSs used intermittently for the management of eczema are safe over periods of up to 5 years.
- A 5-year RCT reported only one episode of skin atrophy in 1213 patients treated with intermittent mild or moderate TCSs (GRADE-assessed as ‘moderate’ certainty), and no cases of clinical adrenal insufficiency were reported in 75 patients in a RCT of intermittent mild or moderate TCSs used for 3 years (GRADE-assessed as ‘moderate’ certainty).
- There was moderate certainty evidence to suggest no increased risk of growth abnormalities, non-skin infections, impaired vaccine response or lymphoma/non-lymphoma malignancies.
- Some ‘very low’ certainty data have provided a potential link between TCSs and lymphoma and type 2 diabetes. These associations warrant further investigation.
- Gaps remain in our understanding of the lifelong effects of TCS use that are difficult to address in high-quality studies.
Conclusions
This review provides some reassuring data for the limited impact of TCS on growth and skin thinning when used intermittently to treat eczema flares over several years. This contrasts with the public perception that these side effects are common and widespread.
Although broadly reassuring, it should be noted that the longest RCT was 5 years in duration and studies were generally underpowered to identify rare events.
There were certain adverse effects that were not reported on in either RCTs or the observational studies, for example topical steroid withdrawal and the effects of TCSs on the eyes. For the adverse effects reported, there was very little information provided regarding the consequences of the adverse effects and whether they resolved after discontinuation of treatment.
Impact on other aspects of the programme
This review did not directly inform other aspects of the programme, as it was completed after the ECO toolkit was completed and tested. However, people with eczema have prioritised the need for better-quality research on the long-term safety of TCSs as a research priority and we hope that this review will stimulate interest in this area.
Workstream 2.4: creation of knowledge tools to support patients and healthcare professionals
This knowledge tool is freely available at www.eczemacareonline.org.uk/en/printables.
Aims
- To develop a knowledge support tool for use in primary care that supports appropriate use of eczema treatments.
- To ensure consistent messaging with and signpost to the ECO toolkit.
Methods
A summary of the key messages from the ECO programme of research (arising from intervention development and summaries of known evidence supporting treatment decisions) was collated into a series of ‘key messages’ for sharing with wider stakeholders and for use in knowledge mobilisation activities.
These key messages were developed with stakeholder input through a series of workshops including:
- A 1-day face-to-face meeting with 34 attendees including researchers (n = 11), healthcare professionals (n = 13), patient partners/organisations (n = 10) (September 2019).
- Five 90-minute online meetings where particular stakeholder views were invited from primary care (n = 4), secondary care (n = 7), pharmacy (n = 5), people with eczema/patient organisations (n = 7) and parents of children with eczema/patient organisations (n = 7) (March 2021).
- A 2-hour online meeting with 18 individuals or patient organisation representatives particularly concerned about a safety concern of eczema treatments termed ‘topical corticosteroid withdrawal’ (May 2021).
The workshops served to clarify the purpose of the key messages, ensure appeal to end users, establish the most appropriate setting for their use, and how they might be used to support clinical care in that setting. Feedback was reviewed through a normalisation process theory (NPT) lens and the key messages were refined and tailored to the target audience, followed by further modification through user testing where members of the public/patients provided feedback.
The final version of the knowledge support tool is shown in Figure 4.
FIGURE 4 Knowledge support tool for using eczema treatments. (Figure not reproduced here; see the original article.)
Key outcomes
- This knowledge tool focuses on the concept of ‘Two Treatments Used Well’ to support people in managing their eczema and understanding how to use their emollients and flare control creams (TCS).
- The infographic will be shared widely with healthcare professionals and through professional societies.
- It serves as an opportunity to ensure consistent messaging between different healthcare professionals and reflects the style and content of the messages in the ECO toolkit.
- It serves as a useful signposting tool for the full ECO website.
Conclusion
We hope this tool will provide a useful tool to support clinical practice and to support patients in navigating their self-care needs. It also provides and alternative avenue for promoting the ECO website.
This knowledge tool is tailored specifically for a UK audience, but the messages it contains are likely to be applicable to most healthcare settings.
Impact on Eczema Care Online intervention and implementation
This knowledge tool has been incorporated into the ECO website and provides a concise, printable version of the key messages contained in the website. It also serves as a signposting tool for the ECO website as it contains the web address and a QR-code link.