Emollients for preventing atopic eczema: Cost-effectiveness analysis of the BEEP trial.

BACKGROUND: Recent discoveries have led to the suggestion that enhancing skin barrier from birth might prevent eczema and food allergy. OBJECTIVE: To determine the cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children at 2 years from a health service perspective. We also considered a 5-year time horizon as a sensitivity analysis. METHODS: A within-trial economic evaluation using data on health resource use and quality of life captured as part of the BEEP trial alongside the trial data. Parents/carers of 1394 infants born to families at high risk of atopic disease were randomised 1:1 to the emollient group, which were advised to apply emollient (Doublebase Gel or Diprobase Cream) to their child at least once daily to the whole body during the first year of life or usual care. Both groups received advice on general skin care. The main economic outcomes were incremental cost-effectiveness ratio (ICER), defined as incremental cost per percentage decrease in risk of eczema in the primary cost-effectiveness analysis. Secondary analysis, undertaken as a cost-utility analysis, reports incremental cost per Quality-Adjusted Life Year (QALY) where child utility was elicited using the proxy CHU-9D at 2 years. RESULTS: At 2 years, the adjusted incremental cost was £87.45 (95% CI -54.31, 229.27) per participant, whilst the adjusted proportion without eczema was 0.0164 (95% CI -0.0329, 0.0656). The ICER was £5337 per percentage decrease in risk of eczema. Adjusted incremental QALYs were very slightly improved in the emollient group, 0.0010 (95% CI -0.0069, 0.0089). At 5 years, adjusted incremental costs were lower for the emollient group, -£106.89 (95% CI -354.66, 140.88) and the proportion without eczema was -0.0329 (95% CI -0.0659, 0.0002). The 5-year ICER was £3201 per percentage decrease in risk of eczema. However, when inpatient costs due to wheezing were excluded, incremental costs were lower and incremental effects greater in the usual care group. CONCLUSIONS: In line with effectiveness endpoints, advice given in the BEEP trial to apply daily emollient during infancy for eczema prevention in high-risk children does not appear cost-effective.

Emollients for prevention of atopic dermatitis: 5-year findings from the BEEP randomized trial.

BACKGROUND: The effectiveness of emollients for preventing atopic dermatitis/eczema is controversial. The Barrier Enhancement for Eczema Prevention trial evaluated the effects of daily emollients during the first year of life on atopic dermatitis and atopic conditions to age 5 years. METHODS: 1394 term infants with a family history of atopic disease were randomized (1:1) to daily emollient plus standard skin-care advice (693 emollient group) or standard skin-care advice alone (701 controls). Long-term follow-up at ages 3, 4 and 5 years was via parental questionnaires. Main outcomes were parental report of a clinical diagnosis of atopic dermatitis and food allergy. RESULTS: Parents reported more frequent moisturizer application in the emollient group through to 5 years. A clinical diagnosis of atopic dermatitis between 12 and 60 months was reported for 188/608 (31%) in the emollient group and 178/631 (28%) in the control group (adjusted relative risk 1.10, 95% confidence interval 0.93 to 1.30). Although more parents in the emollient group reported food reactions in the previous year at 3 and 4 years, cumulative incidence of doctor-diagnosed food allergy by 5 years was similar between groups (92/609 [15%] emollients and 87/632 [14%] controls, adjusted relative risk 1.11, 95% confidence interval 0.84 to 1.45). Findings were similar for cumulative incidence of asthma and hay fever. CONCLUSIONS: Daily emollient application during the first year of life does not prevent atopic dermatitis, food allergy, asthma or hay fever.

The HOME Core outcome set for clinical trials of atopic dermatitis.

Core outcome sets are critically important outcomes that should be measured in clinical trials. Their absence in atopic dermatitis is a form of research waste and impedes combining evidence to inform patient care. Here, we articulate the rationale for core outcome sets in atopic dermatitis and review the work of the international Harmonising Outcome Measures for Eczema group from its inception in Munich, 2010. We describe core domain determination (what should be measured), to instrument selection (how domains should be measured), culminating in the complete core outcome measurement set in Tokyo, 2019. Using a "road map," Harmonising Outcome Measures for Eczema includes diverse research methods including Delphi and nominal group techniques informed by systematic reviews of properties of candidate instruments. The 4 domains and recommended instruments for including in all clinical trials of atopic dermatitis are patient symptoms, measured by Patient-Oriented Eczema Measure and peak Numerical Rating Scale 11 for itch intensity over 24 hours, clinical signs measured using the Eczema Area and Severity Index, quality of life measured by the Dermatology Life Quality Index series for adults, children, and infants, and long-term control measured by either Recap of atopic eczema or Atopic Dermatitis Control Tool.

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

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.

Prescribing and using vitiligo treatments: lessons from a nested process evaluation within the HI-Light vitiligo randomized controlled trial.

BACKGROUND: The HI-Light Trial demonstrated that for active, limited vitiligo, combination treatment with potent topical corticosteroid (TCS) and handheld narrowband ultraviolet B offers a better treatment response than potent TCS alone. However, it is unclear how to implement these findings. AIM: We sought to answer three questions: (i) Can combination treatment be used safely and effectively by people with vitiligo?; (ii) Should combination treatment be made available as routine clinical care?; and (iii) Can combination treatment be integrated within current healthcare provision? METHODS: This was a mixed-methods process evaluation, including semi-structured interviews with a purposive sample of trial participants, structured interviews with commissioners, and an online survey and focus groups with trial staff. Transcripts were coded by framework analysis, with thematic development by multiple researchers. RESULTS: Participants found individual treatments easy to use, but the combination treatment was complicated and required nurse support. Both participants and site investigators felt that combination treatment should be made available, although commissioners were less certain. There was support for the development of services offering combination treatment, although this might not be prioritized above treatment for other conditions. A 'mixed economy' model was suggested, involving patients purchasing their own devices, although concerns regarding the safe use of treatments mean that training, monitoring and ongoing support are essential. The need for medical physics support may mean that a regional service is more practical. CONCLUSION: Combination treatment should be made available for people seeking treatment for vitiligo, but services require partnership with medical physics and ongoing training and support for patients.

Association of frequent moisturizer use in early infancy with the development of food allergy.

BACKGROUND: Food allergy is thought to develop through transcutaneous sensitization, especially in the presence of skin barrier impairment and inflammation. Regular moisturizer application to infant skin could potentially promote transcutaneous sensitization and the development of food allergy. OBJECTIVES: We tested this hypothesis in the Enquiring About Tolerance (EAT) study population. METHODS: The EAT study was a population-based randomized clinical trial conducted from January 15, 2008, to August 31, 2015, and recruited 1303 exclusively breastfed 3-month-old infants and their families from England and Wales. At enrollment at 3 months, families completed a questionnaire that included questions about frequency and type of moisturizer applied, use of corticosteroid creams, and parental report of dry skin or eczema. Infants were examined for visible eczema at the enrollment visit. RESULTS: A statistically significant dose-response relationship was observed between parent-reported moisturization frequency at 3 months of age and the subsequent development of food allergy. Each additional moisturization per week was associated with an adjusted odds ratio of 1.20 (95% CI, 1.13-1.27; P < .0005) for developing food allergy. For infants with no visible eczema at the enrollment visit, the corresponding adjusted odds ratio was 1.18 (95% CI, 1.07-1.30; P = .001) and for those with eczema at the enrollment visit, 1.20 (95% CI, 1.11-1.31; P < .0005). Moisturizer frequency showed similar dose-response relationships with the development of both food and aeroallergen sensitization at 36 months. CONCLUSIONS: These findings support the notion that regular application of moisturizers to the skin of young infants may promote the development of food allergy through transcutaneous sensitization.

Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial.

BACKGROUND: Skin barrier dysfunction precedes eczema development. We tested whether daily use of emollient in the first year could prevent eczema in high-risk children. METHODS: We did a multicentre, pragmatic, parallel-group, randomised controlled trial in 12 hospitals and four primary care sites across the UK. Families were approached via antenatal or postnatal services for recruitment of term infants (at least 37 weeks' gestation) at high risk of developing eczema (ie, at least one first-degree relative with parent-reported eczema, allergic rhinitis, or asthma, diagnosed by a doctor). Term newborns with a family history of atopic disease were randomly assigned (1:1) to application of emollient daily (either Diprobase cream or DoubleBase gel) for the first year plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). The randomisation schedule was created using computer-generated code (stratified by recruiting centre and number of first-degree relatives with atopic disease) and participants were assigned to groups using an internet-based randomisation system. The primary outcome was eczema at age 2 years (defined by UK working party criteria) with analysis as randomised regardless of adherence to allocation for participants with outcome data collected, and adjusting for stratification variables. This trial is registered with ISRCTN, ISRCTN21528841. Data collection for long-term follow-up is ongoing, but the trial is closed to recruitment. FINDINGS: 1394 newborns were randomly assigned to study groups between Nov 19, 2014, and Nov 18, 2016; 693 were assigned to the emollient group and 701 to the control group. Adherence in the emollient group was 88% (466 of 532) at 3 months, 82% (427 of 519) at 6 months, and 74% (375 of 506) at 12 months in those with complete questionnaire data. At age 2 years, eczema was present in 139 (23%) of 598 infants with outcome data collected in the emollient group and 150 (25%) of 612 infants in the control group (adjusted relative risk 0·95 [95% CI 0·78 to 1·16], p=0·61; adjusted risk difference -1·2% [-5·9 to 3·6]). Other eczema definitions supported the results of the primary analysis. Mean number of skin infections per child in year 1 was 0·23 (SD 0·68) in the emollient group versus 0·15 (0·46) in the control group; adjusted incidence rate ratio 1·55 (95% CI 1·15 to 2·09). INTERPRETATION: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest an increased risk of skin infections. Our study shows that families with eczema, asthma, or allergic rhinitis should not use daily emollients to try and prevent eczema in their newborn. FUNDING: National Institute for Health Research Health Technology Assessment.

Clinical examination for hyperlinear palms to determine filaggrin genotype: A diagnostic test accuracy study.

BACKGROUND: Palmar hyperlinearity is a feature of ichthyosis vulgaris, the monogenic skin disorder caused by FLG loss-of-function mutations. OBJECTIVE: To investigate how well the presence or absence of hyperlinear palms (HLP) detect FLG genotype in children. METHODS: STARD criteria are used to report this diagnostic accuracy study. Phenotype and genotype data (four most prevalent FLG null mutations) were obtained from a total of 3656 children in three studies: the UK CLOTHES trial (children 1-5 years with moderate-severe atopic eczema); UK BEEP trial (2 year olds at high risk of developing atopic eczema); UK-Irish eczema case collection (0-16 year olds with atopic eczema). All participants included in analyses of HLP as the index test and FLG genotype as the reference were of white European ancestry. RESULTS: Thirty-two percent of participants (1159/3656) had FLG null mutation(s) and 37% (1347/3656) had HLP. In 13% (464/3656), HLP was recorded as 'unsure' or not recorded. The sensitivity and specificity of HLP for detecting FLG mutations in each of the studies was: 67% (95% CI 55-78%) and 75% (67-82%) in CLOTHES; 46% (36-55%) and 89% (86-91%) in BEEP; 72% (68-75%) and 60% (57-62%) in the UK-Irish case collection. Positive and negative likelihood ratios were: 2.73 (1.95-3.81) and 0.44 (0.31-0.62) in CLOTHES; 4.02 (2.99-5.40) and 0.61 (0.52-0.73) in BEEP; 1.79 (1.66-1.93) and 0.47 (0.42-0.53) in the UK-Irish collection. DISCUSSION: Trained observers were able to define palmar hyperlinearity in the majority (3191/3656, 87%) of cases. The presence of HLP is not a reliable sign to detect FLG mutations, but the absence of HLP excludes FLG null genotype with a reasonable degree of certainty.

Test-guided dietary management of eczema in children: A randomized controlled feasibility trial (TEST).

BACKGROUND: Parents commonly ask about food allergy tests, to find a cause for their child's eczema, yet the value of routine testing is uncertain. OBJECTIVE: To determine whether a clinical trial comparing test-guided dietary advice versus usual care, for the management of eczema, is feasible. METHODS: Children (>3 months and <5 years) with mild-to-severe eczema, recruited via primary care, were individually randomized (1:1) to intervention or usual care. Intervention participants underwent structured allergy history and skin prick tests (SPT) with dietary advice for cow's milk, hen's egg, wheat, peanut, cashew and codfish. All participants were followed up for 24 weeks. A sample of doctors and parents was interviewed. Registration ISRCTN15397185. RESULTS: From 1059 invitation letters sent to carers of potentially eligible children, 84 were randomized (42 per group) with mean age of 32.4 months (SD 13.9) and POEM of 8.7 (4.8). Of the 42, 6 (14%) intervention participants were advised to exclude one or more foods, most commonly egg, peanut or milk. By participant, 1/6 had an oral food challenge (negative); 3/6 were told to exclude until review in allergy clinic; and 6/6 advised a home dietary trial (exclusion and reintroduction of food over 4-6 weeks) - with 1/6 partially completing it. Participant retention (four withdrawals) and data completeness (74%-100%) were acceptable and contamination low (two usual care participants had allergy tests). There were three minor SPT-related adverse events. During follow-up, 12 intervention and 8 usual care participants had minor, unrelated adverse events plus one unrelated hospital admission. CONCLUSIONS: It is possible to recruit, randomize and retain children with eczema from primary care into a trial of food allergy screening and to collect the outcomes of interest. Changes to recruitment and inclusion criteria are needed in a definitive trial, to ensure inclusion of younger children from more diverse backgrounds.

Skincare interventions in infants for preventing eczema and food allergy: A cochrane systematic review and individual participant data meta-analysis.

OBJECTIVE: Eczema and food allergy start in infancy and have shared genetic risk factors that affect skin barrier. We aimed to evaluate whether skincare interventions can prevent eczema or food allergy. DESIGN: A prospectively planned individual participant data meta-analysis was carried out within a Cochrane systematic review to determine whether skincare interventions in term infants prevent eczema or food allergy. DATA SOURCES: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and trial registries to July 2020. ELIGIBILITY CRITERIA FOR SELECTED STUDIES: Included studies were randomized controlled trials of infants <1 year with healthy skin comparing a skin intervention with a control, for prevention of eczema and food allergy outcomes between 1 and 3 years. RESULTS: Of the 33 identified trials, 17 trials (5823 participants) had relevant outcome data and 10 (5154 participants) contributed to IPD meta-analysis. Three of seven trials contributing to primary eczema analysis were at low risk of bias, and the single trial contributing to primary food allergy analysis was at high risk of bias. Interventions were mainly emollients, applied for the first 3-12 months. Skincare interventions probably do not change risk of eczema by age 1-3 years (RR 1.03, 95% CI 0.81, 1.31; I2 =41%; moderate certainty; 3075 participants, 7 trials). Sensitivity analysis found heterogeneity was explained by increased eczema in a trial of daily bathing as part of the intervention. It is unclear whether skincare interventions increase risk of food allergy by age 1-3 years (RR 2.53, 95% CI 0.99 to 6.47; very low certainty; 996 participants, 1 trial), but they probably increase risk of local skin infections (RR 1.34, 95% CI 1.02, 1.77; I2 =0%; moderate certainty; 2728 participants, 6 trials). CONCLUSION: Regular emollients during infancy probably do not prevent eczema and probably increase local skin infections.

Skin care interventions in infants for preventing eczema and food allergy.

BACKGROUND: Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective in preventing eczema or food allergy. OBJECTIVES: Primary objective To assess effects of skin care interventions, such as emollients, for primary prevention of eczema and food allergy in infants Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy. SEARCH METHODS: We searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials. SELECTION CRITERIA: RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required. DATA COLLECTION AND ANALYSIS: This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured by the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen. MAIN RESULTS: This review identified 33 RCTs, comprising 25,827 participants. A total of 17 studies, randomising 5823 participants, reported information on one or more outcomes specified in this review. Eleven studies randomising 5217 participants, with 10 of these studies providing IPD, were included in one or more meta-analysis (range 2 to 9 studies per individual meta-analysis). Most studies were conducted at children's hospitals. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported our outcomes, 13 assessed emollients. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to two years. We assessed most of this review's evidence as low certainty or had some concerns of risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. Evidence for the primary food allergy outcome was rated as high risk of bias due to inclusion of only one trial where findings varied when different assumptions were made about missing data. Skin care interventions during infancy probably do not change risk of eczema by one to two years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; moderate-certainty evidence; 3075 participants, 7 trials) nor time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). It is unclear whether skin care interventions during infancy change risk of IgE-mediated food allergy by one to two years of age (RR 2.53, 95% CI 0.99 to 6.47; 996 participants, 1 trial) or allergic sensitisation to a food allergen at age one to two years (RR 0.86, 95% CI 0.28 to 2.69; 1055 participants, 2 trials) due to very low-certainty evidence for these outcomes. Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial). However, this was only seen for cow's milk, and may be unreliable due to significant over-reporting of cow's milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.34, 95% CI 1.02 to 1.77; moderate-certainty evidence; 2728 participants, 6 trials) and may increase risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) or stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although confidence intervals for slippages and stinging/allergic reactions are wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses show that effects of interventions were not influenced by age, duration of intervention, hereditary risk, FLG mutation,  or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and risk of developing eczema or food allergy. AUTHORS' CONCLUSIONS: Skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema, and probably increase risk of skin infection. Effects of skin care interventions on risk of food allergy are uncertain. Further work is needed to understand whether different approaches to infant skin care might promote or prevent eczema and to evaluate effects on food allergy based on robust outcome assessments.

An algorithm for diagnosing IgE-mediated food allergy in study participants who do not undergo food challenge.

BACKGROUND: Food allergy diagnosis in clinical studies can be challenging. Oral food challenges (OFC) are time-consuming, carry some risk and may, therefore, not be acceptable to all study participants. OBJECTIVE: To design and evaluate an algorithm for detecting IgE-mediated food allergy in clinical study participants who do not undergo OFC. METHODS: An algorithm for trial participants in the Barrier Enhancement for Eczema Prevention (BEEP) study who were unwilling or unable to attend OFC was developed. BEEP is a pragmatic, multi-centre, randomized-controlled trial of daily emollient for the first year of life for primary prevention of eczema and food allergy in high-risk infants (ISRCTN21528841). We built on the European iFAAM consensus guidance to develop a novel food allergy diagnosis algorithm using available information on previous allergenic food ingestion, food reaction(s) and sensitization status. This was implemented by a panel of food allergy experts blind to treatment allocation and OFC outcome. We then evaluated the algorithm's performance in both BEEP and Enquiring About Tolerance (EAT) study participants who did undergo OFC. RESULTS: In 31/69 (45%) BEEP and 44/55 (80%) EAT study control group participants who had an OFC the panel felt confident enough to categorize children as "probable food allergy" or "probable no food allergy". Algorithm-derived panel decisions showed high sensitivity 94% (95%CI 68, 100) BEEP; 90% (95%CI 72, 97) EAT and moderate specificity 67% (95%CI 39, 87) BEEP; 67% (95%CI 39, 87) EAT. Sensitivity and specificity were similar when all BEEP and EAT participants with OFC outcome were included. CONCLUSION: We describe a new algorithm with high sensitivity for IgE-mediated food allergy in clinical study participants who do not undergo OFC. CLINICAL RELEVANCE: This may be a useful tool for excluding food allergy in future clinical studies where OFC is not conducted.

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.

Navigating the landscape of core outcome set development in dermatology.

The development of core outcome sets (COSs; ie, a minimum set of core outcomes that should be measured and reported in all trials or in clinical practice for a specific condition) in dermatology is increasing in pace. A total of 44 dermatology-related COS projects have been registered in the online Core Outcome Measures in Effectiveness Trials database (http://www.comet-initiative.org/studies/search) and include studies on 26 different skin diseases. With the increasing number of COSs in dermatology, care is needed to ensure the delivery of high-quality COSs that meet quality standards when using state-of-the-art methods. In 2015, the Cochrane Skin-Core Outcome Set Initiative (CS-COUSIN) was established. CS-COUSIN is an international, multidisciplinary working group aiming to improve the development and implementation of COSs in dermatology. CS-COUSIN has developed guidance on how to develop high-quality COSs for skin diseases and supports dermatology-specific COS initiatives. Currently, 17 COS development groups are affiliated with CS-COUSIN and following standardized COS development processes. To ensure successful uptake of COSs in dermatology, researchers, clinicians, systematic reviewers, guideline developers, and other stakeholders should use existing COSs in their work.

Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial.

BACKGROUND: Bullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids. METHODS: We did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3-9, 10-30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1-3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3-5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604. FINDINGS: Between March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1-26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9-30·1), p=0·001. INTERPRETATION: Starting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term. FUNDING: NIHR Health Technology Assessment Programme.

What Factors are Important to Patients when Assessing Treatment Response: An International Cross-sectional Survey.

This study investigated the perspective of international patients on individual symptoms of atopic dermatitis (eczema) in determining treatment response. A questionnaire was developed to evaluate the importance of symptoms from the patient's perspective. Patients were asked: "How important are these features in deciding whether or not a treatment is working?", and rated symptoms on a 5-point Likert scale. Patients were approached via Harmonising Outcome Measures for Eczema (HOME) collaborators and self-selected to take part in the on-line survey. Patients from 34 countries (n = 1,111) completed the survey; of these, 423 (38.3%) were parents of children with eczema. Nine items were rated as being "quite important" or "very important" by more than 80% of the respondents: itch, pain/soreness, skin feels hot or inflamed, bleeding, involvement of visible or sensitive body sites, cracks, sleep difficulties, amount of body affected, and weeping/oozing. These results may be of use in determining the face validity of scales from a cross-cultural patients' perspective.

Penicillin to prevent recurrent leg cellulitis.

BACKGROUND: Cellulitis of the leg is a common bacterial infection of the skin and underlying tissue. We compared prophylactic low-dose penicillin with placebo for the prevention of recurrent cellulitis. METHODS: We conducted a double-blind, randomized, controlled trial involving patients with two or more episodes of cellulitis of the leg who were recruited in 28 hospitals in the United Kingdom and Ireland. Randomization was performed according to a computer-generated code, and study medications (penicillin [250 mg twice a day] or placebo for 12 months) were dispensed by a central pharmacy. The primary outcome was the time to a first recurrence. Participants were followed for up to 3 years. Because the risk of recurrence was not constant over the 3-year period, the primary hypothesis was tested during prophylaxis only. RESULTS: A total of 274 patients were recruited. Baseline characteristics were similar in the two groups. The median time to a first recurrence of cellulitis was 626 days in the penicillin group and 532 days in the placebo group. During the prophylaxis phase, 30 of 136 participants in the penicillin group (22%) had a recurrence, as compared with 51 of 138 participants in the placebo group (37%) (hazard ratio, 0.55; 95% confidence interval [CI], 0.35 to 0.86; P=0.01), yielding a number needed to treat to prevent one recurrent cellulitis episode of 5 (95% CI, 4 to 9). During the no-intervention follow-up period, there was no difference between groups in the rate of a first recurrence (27% in both groups). Overall, participants in the penicillin group had fewer repeat episodes than those in the placebo group (119 vs. 164, P=0.02 for trend). There was no significant between-group difference in the number of participants with adverse events (37 in the penicillin group and 48 in the placebo group, P=0.50). CONCLUSIONS: In patients with recurrent cellulitis of the leg, penicillin was effective in preventing subsequent attacks during prophylaxis, but the protective effect diminished progressively once drug therapy was stopped. (Funded by Action Medical Research; PATCH I Controlled-Trials.com number, ISRCTN34716921.).

Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention.

BACKGROUND: Atopic dermatitis (atopic eczema) is a chronic inflammatory skin disease that has reached epidemic proportions in children worldwide and is increasing in prevalence. Because of the significant socioeconomic effect of atopic dermatitis and its effect on the quality of life of children and families, there have been decades of research focused on disease prevention, with limited success. Recent advances in cutaneous biology suggest skin barrier defects might be key initiators of atopic dermatitis and possibly allergic sensitization. OBJECTIVE: Our objective was to test whether skin barrier enhancement from birth represents a feasible strategy for reducing the incidence of atopic dermatitis in high-risk neonates. METHODS: We performed a randomized controlled trial in the United States and United Kingdom of 124 neonates at high risk for atopic dermatitis. Parents in the intervention arm were instructed to apply full-body emollient therapy at least once per day starting within 3 weeks of birth. Parents in the control arm were asked to use no emollients. The primary feasibility outcome was the percentage of families willing to be randomized. The primary clinical outcome was the cumulative incidence of atopic dermatitis at 6 months, as assessed by a trained investigator. RESULTS: Forty-two percent of eligible families agreed to be randomized into the trial. All participating families in the intervention arm found the intervention acceptable. A statistically significant protective effect was found with the use of daily emollient on the cumulative incidence of atopic dermatitis with a relative risk reduction of 50% (relative risk, 0.50; 95% CI, 0.28-0.9; P = .017). There were no emollient-related adverse events and no differences in adverse events between groups. CONCLUSION: The results of this trial demonstrate that emollient therapy from birth represents a feasible, safe, and effective approach for atopic dermatitis prevention. If confirmed in larger trials, emollient therapy from birth would be a simple and low-cost intervention that could reduce the global burden of allergic diseases.

How should an incident case of atopic dermatitis be defined? A systematic review of primary prevention studies.

BACKGROUND: Eczema prevention is now an active area of dermatologic and allergy research. Defining an incident case is therefore a prerequisite for such a study. OBJECTIVE: We sought to examine how an incident case of atopic dermatitis was defined in previous atopic dermatitis prevention studies in order to make recommendations on a standard definition of new atopic dermatitis cases for use in future prevention trials. METHODS: We conducted a systematic review of controlled interventional atopic dermatitis prevention studies by using searches of MEDLINE and Cochrane databases for studies published from 1980 to the end of January 2011. Studies that included atopic dermatitis as a secondary outcome, such as asthma prevention trials, were included. RESULTS: One hundred two studies were included in the final analysis, of which 27 (26.5%) did not describe any criteria for defining an incident case of atopic dermatitis. Of the remaining 75 studies with reported disease criteria, the Hanifin-Rajka criteria were the most commonly used (28 studies). A disease definition unique to that particular study (21 studies) was the second most commonly used disease definition, although the sources for such novel definitions were not cited. CONCLUSIONS: The results from this systematic review highlight the need for improved reporting and standardization of the definition used for an incident case in atopic dermatitis prevention studies. Most prevention studies have used disease definitions such as the Hanifin-Rajka criteria that include disease chronicity. While acceptable for cumulative incidence outcomes, inclusion of disease chronicity precludes the precise measurement of disease onset. We propose a definition based on existing scientific studies that could be used in future prospective studies.