Safety of topical corticosteroids in atopic eczema:an umbrella review

Objective: An umbrella review summarising all safety data from systematic reviews of topical corticosteroids (TCS) in adults and children with atopic eczema .Methods: Embase, MEDLINE, PubMed, Cochrane Database of Systematic Reviews and the Centre of Evidence Based Dermatology map of eczema systematic reviews searched until 7th November 2018 and Epistemonikos until 2nd March 2021. Reviews were included if they assessed safety of TCS in atopic eczema and searched >1 database using a reproducible search strategy. Review quality assessed using AMSTAR-2. PROSPERO registration: CRD42018079409. Results: 38 systematic reviews included, 34 low/critically low quality. Treatment and follow-up usually short (2-4 weeks). Key findings: TCS versus emollient/vehicle: No meta-analyses identified for skin-thinning. Two 2-week randomised controlled trials (RCTs) found no significant increased risk with very potent TCS (0/196 TCS vs 0/33 vehicle in children and 6/109 TCS vs 2/50 vehicle, age unknown). Biochemical adrenal suppression (cortisol) was 3.8% (95% CI 2.4%-5.8%) in a meta-analysis of 11 uncontrolled observational studies (any potency TCS, 522 children). Effects reversed when treatment ceased. TCS versus topical calcineurin inhibitors (TCIs): Meta-analysis showed higher relative risk of skin-thinning with TCS (RR 4.86, 95% CI 1.06-22.28, n=4128, four RCTs, including one 5-year RCT). Eight cases in 2068 participants, 7 using potent TCS. No evidence of growth suppression.Once daily versus more frequent TCS: No meta-analyses identified. No skin-thinning in one RCT (3 weeks potent TCS, n=94) or biochemical adrenal suppression in two RCTs (up to 2 weeks very potent/moderate TCS, n=129).TCS twice/week to prevent flares (‘weekend therapy’) versus vehicle: No meta-analyses identified. No evidence of skin-thinning in five RCTs. One RCT found biochemical adrenal suppression (2/44 children, potent TCS).Conclusions: We found no evidence of harm when TCS used intermittently “as required” to treat flares or “weekend therapy” to prevent flares. However, long-term safety data was limited

Investing in updating: how do conclusions change when Cochrane systematic reviews are updated?

BACKGROUND: Cochrane systematic reviews aim to provide readers with the most up-to-date evidence on the effects of healthcare interventions. The policy of updating Cochrane reviews every two years consumes valuable time and resources and may not be appropriate for all reviews. The objective of this study was to examine the effect of updating Cochrane systematic reviews over a four year period. METHODS: This descriptive study examined all completed systematic reviews in the Cochrane Database of Systematic Reviews (CDSR) Issue 2, 1998. The latest version of each of these reviews was then identified in CDSR Issue 2, 2002 and changes in the review were described. For reviews that were updated within this time period and had additional studies, we determined whether their conclusion had changed and if there were factors that were predictive of this change. RESULTS: A total of 377 complete reviews were published in CDSR Issue 2, 1998. In Issue 2, 2002, 14 of these reviews were withdrawn and one was split, leaving 362 reviews to examine for the purpose of this study. Of these reviews, 254 (70%) were updated. Of these updated reviews, 23 (9%) had a change in conclusion. Both an increase in precision and a change in statistical significance of the primary outcome were predictive of a change in conclusion of the review. CONCLUSION: The concerns around a lack of updating for some reviews may not be justified considering the small proportion of updated reviews that resulted in a changed conclusion. A priority-setting approach to the updating of Cochrane systematic reviews may be more appropriate than a time-based approach. Updating all reviews as frequently as every two years may not be necessary, however some reviews may need to be updated more often than every two years

What are the main inefficiencies in trial conduct : a survey of UKCRC registered clinical trials units in the UK

BACKGROUND: The UK Clinical Research Collaboration (UKCRC) registered Clinical Trials Units (CTUs) Network aims to support high-quality, efficient and sustainable clinical trials research in the UK. To better understand the challenges in efficient trial conduct, and to help prioritise tackling these challenges, we surveyed CTU staff. The aim was to identify important inefficiencies during two key stages of the trial conduct life cycle: (i) from grant award to first participant, (ii) from first participant to reporting of final results. METHODS: Respondents were asked to list their top three inefficiencies from grant award to recruitment of the first participant, and from recruitment of the first participant to publication of results. Free text space allowed respondents to explain why they thought these were important. The survey was constructed using SurveyMonkey and circulated to the 45 registered CTUs in May 2013. Respondents were asked to name their unit and job title, but were otherwise anonymous. Free-text responses were coded into broad categories. RESULTS: There were 43 respondents from 25 CTUs. The top inefficiency between grant award and recruitment of first participant was reported as obtaining research and development (R&D) approvals by 23 respondents (53%), contracts by 22 (51%), and other approvals by 13 (30%). The top inefficiency from recruitment of first participant to publication of results was failure to meet recruitment targets, reported by 19 (44%) respondents. A common comment was that this reflected overoptimistic or inaccurate estimates of recruitment at site. Data management, including case report form design and delays in resolving data queries with sites, was reported as an important inefficiency by 11 (26%) respondents, and preparation and submission for publication by 9 (21%). CONCLUSIONS: Recommendations for improving the efficiency of trial conduct within the CTUs network include: further reducing unnecessary bureaucracy in approvals and contracting; improving training for site staff; realistic recruitment targets and appropriate feasibility; developing training across the network; improving the working relationships between chief investigators and units; encouraging funders to release sufficient funding to allow prompt recruitment of trial staff; and encouraging more research into how to improve the efficiency and quality of trial conduct

Different strategies for using topical corticosteroids in people with eczema

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To establish the effectiveness and safety of different ways of using topical corticosteroids in people with eczema

Long-term oral prednisolone exposure in primary care for bullous pemphigoid: population-based study

Background Oral prednisolone is the mainstay treatment for bullous pemphigoid, an autoimmune blistering skin disorder affecting older people. Treatment with moderate-to-high doses is often initiated in secondary care, but then continued in primary care. Aim To describe long-term oral prednisolone prescribing in UK primary care for adults with bullous pemphigoid from 1998 to 2017. Design and setting A prospective cohort study using routinely collected data from the Clinical Practice Research Datalink, a primary care database containing the healthcare records for over 17 million people in the UK. Method Oral prednisolone exposure was characterised in terms of the proportion of individuals with incident bullous pemphigoid prescribed oral prednisolone following their diagnosis, and the duration and dose of prednisolone. Results In total, 2312 (69.6%) of 3322 people with bullous pemphigoid were prescribed oral prednisolone in primary care. The median duration of exposure was 10.6 months (interquartile range [IQR] 3.4-24.0). Of prednisolone users, 71.5% were continuously exposed for >3 months, 39.7% for >1 year, 14.7% for >3 years, 5.0% for >5 years, and 1.7% for >10 years. The median cumulative dose was 2974 mg (IQR 1059-6456). Maximum daily doses were ≥10 mg/day in 74.4% of prednisolone users, ≥20 mg/day in 40.7%, ≥30 mg/day in 18.2%, ≥40 mg/day in 6.6%, ≥50 mg/day in 3.8%, and ≥60 mg/day in 1.9%. Conclusion A high proportion of people with incident bullous pemphigoid are treated with oral prednisolone in UK primary care. Action is required by primary and second care services to encourage use of steroid-sparing alternatives and, where switching is not possible, ensure prophylactic treatments and proactive monitoring of potential side effects are in place

Strategies for measuring long-term control in atopic dermatitis trials: a systematic review

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease. There are no standardised methods for capturing long-term control of AD. Objective: To identify how long-term control has been captured in published randomised controlled trials (RCTs). Resultswill initiate consensus discussions on how best to measure long-term control in the core outcome set for AD. Methods: Systematic review of RCTs of AD treatments published between 2000 and 2013, with a follow-up period of ≥3 months, at least one outcome measure recorded at ≥3 time-points, full paper available, and published in English. Results: 101/ 353 RCTs were eligible. Methods to capture long-term control included: repeated measurement of AD outcomes (92 RCTs; 91%), use of AD medication (29 RCTs; 28.7%); and AD flares/remissions (26 RCTs; 25.7%). Repeated measurements of AD outcomes were typically collected 3 to 5 times during a trial, but analysis methods often failed to make best use of the data. Time to first flare was most commonly for trials including flare data (21/52). Medication-use was recorded based on quantity, potency and frequency of application. Limitations: Included RCT data only Conclusion: This review illustrates the difficulties in measuring long-term control, and points to the need for improved harmonization of outcomes

Supporting families managing childhood eczema:Developing and optimising Eczema Care Online using qualitative research

Background: childhood eczema is often poorly controlled due to under-use of emollients and topical corticosteroids. Parents/carers report practical and psychosocial barriers to managing their child’s eczema, including child resistance. Online interventions could potentially support parents/carers; however, rigorous research developing such interventions has been limited. Aim: to develop an online behavioural intervention to help parents/carers manage and co-manage their child’s eczema. Design and setting: Intervention development using a theory-, evidence- and Person-Based Approach with qualitative research. Methods: a systematic review and qualitative synthesis (32 studies) and interviews with parents/carers (N=30) were used to identify barriers and facilitators to effective eczema management, and a prototype intervention was developed. Think-aloud interviews with parents/carers (N=25) were then used to optimise the intervention to increase its acceptability and feasibility. Results: qualitative research identified that parents/carers had concerns about using emollients and topical corticosteroids; incomplete knowledge and skills around managing eczema; and reluctance to transitioning to co-managing eczema with their child. Think-aloud interviews highlighted that while experienced parents/carers felt they knew how to manage eczema, some information about how to use treatments was still new. Techniques for addressing barriers included: providing a rationale explaining how emollients and topical corticosteroids work; demonstrating how to use treatments; and highlighting that the intervention provided new, up-to-date information. Conclusions: parents/carers need support in effectively managing and co-managing their child’s eczema. The key output of this research is Eczema Care Online (ECO) for Families; an online intervention for parents/carers of children with eczema, which is being evaluated in a randomised trial

The possibility of critical realist randomised controlled trials.

BACKGROUND: Some realists have criticised randomised controlled trials for their inability to explain the causal relations that they identify; to take into account the influence of the social context of the interventions they evaluate; and to account for individual difference. However, among realists, there is controversy over whether it is possible to improve trials by making them realist, or whether realism and the philosophical assumptions underlying trials are incompatible. This paper contributes to the debate in Trials on this issue. The debate thus far has concentrated on the possibility of combining trial methodology with that of realist evaluation. MAIN BODY: We concur with the contention that it is not feasible to combine randomised controlled trial design with the realist evaluation approach. However, we argue that a different variant of realism, critical realism, provides a more appropriate theoretical grounding for realist trials. In contrast to realist evaluation, which regards social mechanisms as an amalgam of social resources and people's reasoning, critical realism insists on their distinction. It does so on the basis of its assertion of the need to distinguish between social structures (in which resources lie) and human agency (which is at least partly guided by reasoning). From this perspective, conceiving of social mechanisms as external to participants can be seen as a valid methodological strategy for supplementing the exclusive concentration of trials on outcomes. While accepting realist evaluation's insistence that causality in open systems involves a configuration of multiple generative mechanisms, we adopt the critical realist interpretation of the experimental method, which sees it as creating artificial closure in order to identify the effects of specific causal mechanisms. If randomised controlled trials can be regarded as epidemiological proxies that substitute probabilistic controls over extraneous factors for closed experiments, their examination of the powers of discrete mechanisms through observation of the variation of outcomes is appropriate. CONCLUSION: While there are still issues to be resolved, critical realist randomised controlled trials are possible and have the potential to overcome some of the difficulties faced by traditional trial designs in accounting for the influence of social context and individual interpretation

Measuring atopic eczema symptoms in clinical practice: The first consensus statement from the Harmonising Outcome Measures for Eczema in clinical practice initiative

Background: Measuring patient-centered outcomes in clinical practice is valuable for monitoring patients and advancing real-world research. A new initiative from the Harmonising Outcome Measures for Eczema (HOME) group aims to recommend what might be recorded for atopic eczema patients in routine clinical care. Objectives: Prioritize outcome domains to measure atopic eczema in clinical practice and select valid and practical outcome measurement instruments for the highest-priority domain. Methods: An online survey of HOME members identified and ranked 21 possible health domains. Suitable instruments were then selected for the top-prioritized domain at the HOME VI meeting, using established consensus processes informed by systematic reviews of instrument quality. Results: Patient-reported symptoms was the top-prioritized domain. In accordance with psychometric properties and feasibility, there was consensus that the recommended instruments to measure atopic eczema symptoms in clinical practice are the POEM, the PO-SCORAD index, or both. The numeric rating scale for itch received support pending definition and validation in atopic eczema. Conclusion: Following the first step of the HOME Clinical Practice initiative, we endorse using the POEM, the PO-SCORAD index, or both for measuring atopic eczema symptoms in clinical practice. Additional high-priority domains for clinical practice will be assessed at subsequent HOME meetings