Effectiveness and cost-effectiveness of daily all-over-body application of emollient during the first year of life for preventing atopic eczema in high-risk children (The BEEP trial): protocol for a randomised controlled trial.

BACKGROUND: Atopic eczema (AE) is a common skin problem that impairs quality of life and is associated with the development of other atopic diseases including asthma, food allergy and allergic rhinitis. AE treatment is a significant cost burden for health care providers. The purpose of the trial is to investigate whether daily application of emollients for the first year of life can prevent AE developing in high-risk infants (first-degree relative with asthma, AE or allergic rhinitis). METHODS: This is a protocol for a pragmatic, two-arm, randomised controlled, multicentre trial. Up to 1400 term infants at high risk of developing AE will be recruited through the community, primary and secondary care in England. Participating families will be randomised in a 1:1 ratio to receive general infant skin-care advice, or general skin-care advice plus emollients with advice to apply daily to the infant for the first year of life. Families will not be blinded to treatment allocation. The primary outcome will be a blinded assessment of AE at 24 months of age using the UK Working Party Diagnostic Criteria for Atopic Eczema. Secondary outcomes are other definitions of AE, time to AE onset, severity of AE (EASI and POEM), presence of other allergic diseases including food allergy, asthma and hay fever, allergic sensitisation, quality of life, cost-effectiveness and safety of the emollients. Subgroup analyses are planned for the primary outcome according to filaggrin genotype and the number of first-degree relatives with AE and other atopic diseases. Families will be followed up by online and postal questionnaire at 3, 6, 12 and 18 months with a face-to-face visit at 24 months. Long-term follow-up until 60 months will be via annual questionnaires. DISCUSSION: This trial will demonstrate whether skin-barrier enhancement through daily emollient for the first year of life can prevent AE from developing in high-risk infants. If effective, this simple and cheap intervention has the potential to result in significant cost savings for health care providers throughout the world by preventing AE and possibly other associated allergic diseases. TRIAL REGISTRATION: ISRCTN registry; ID: ISRCTN21528841 . Registered on 25 July 2014

Standardized reporting of the Eczema Area and Severity Index (EASI) and the Patient-Oriented Eczema Measure (POEM): a recommendation by the Harmonising Outcome Measures for Eczema (HOME) Initiative

Several organizations from multiple fields of medicine are setting standards for clinical research including protocol development,1 harmonization of outcome reporting,2 statistical analysis,3 quality assessment4 and reporting of findings.1 Clinical research standardization facilitates the interpretation and synthesis of data, increases the usability of trial results for guideline groups and shared decision‐making, and reduces selective outcome reporting bias. The mission of the Harmonising Outcome Measures for Eczema (HOME) initiative is to establish an agreed‐upon core set of outcomes to be measured and reported in all clinical trials of atopic dermatitis (AD)

Assessment of hydropyrolysis as a method for the quantification of black carbon using standard reference materials

A wide selection of thermal, chemical and optical methods have been proposed for the quantification of black carbon (BC) in environmental matrices, and the results to date differ markedly depending upon the method used. A new approach is hydropyrolysis (hypy), where pyrolysis assisted by high hydrogen pressures (150 bar) facilitates the complete reductive removal of labile organic matter, so isolating a highly stable portion of the BC continuum (defined as BChypy). Here, the potential of hypy for the isolation and quantification of BC is evaluated using the 12 reference materials from the International BC Ring Trial, comprising BC-rich samples, BC-containing environmental matrices and BC-free potentially interfering materials. By varying the hypy operating conditions, it is demonstrated that lignocellulosic, humic and other labile organic carbon material (defined as non-BChypy) is fully removed by 550 °C, with hydrogasification of the remaining BChypy not commencing until over 575 °C. The resulting plateau in sample mass and carbon loss is apparent in all of the environmental samples, facilitating BC quantification in a wide range of materials. The BChypy contents for all 12 ring trial samples fall within the range reported in the BC inter-comparison study, and systematic differences with other methods are rationalised. All methods for BC isolation, including hypy are limited by the fact that BC cannot be distinguished from extremely thermally mature organic matter; for example in high rank coals. However, the data reported here indicates that BChypy has an atomic H/C ratio of less than 0.5 and therefore comprises a chemically well-defined polyaromatic structure in terms of the average size of peri-condensed aromatic clusters of >7 rings (24 carbon atoms), that is consistent across different sample matrices. This, together with the sound underlying rationale for the reductive removal of labile organic matter, makes hypy an ideal approach for matrix independent BC quantification. The hypy results are extremely reproducible, with BChypy determinations from triplicate analyses typically within ±2% across all samples, limited mainly by the precision of the elemental analyser

Tralokinumab provides clinically meaningful responses at week 16 in adults with moderate-to-severe atopic dermatitis who do not achieve IGA 0/1

Background and Objective: Investigator’s Global Assessment of clear/almost clear skin (IGA 0/1) is a difficult endpoint to achieve after short-term treatment of chronic moderate-to-severe atopic dermatitis, and does not fully reflect clinically meaningful changes in other parameters. We assessed the impact of tralokinumab versus placebo on other clinically meaningful parameters in patients not achieving IGA 0/1 at week 16 using pooled data from two monotherapy phase III trials, ECZTRA 1 and 2. Methods: This post hoc analysis included patients (n = 1328) from ECZTRA 1 and 2 who did not achieve the co-primary endpoint, IGA 0/1 at week 16 without rescue medication. Endpoints evaluating atopic dermatitis extent and severity included proportions of patients achieving IGA 0/1, 50%, 75%, and 90% improvement in Eczema Area and Severity Index (EASI-50/75/90); endpoints evaluating patient-reported outcomes included a ≥ 3-point improvement in worst daily pruritus Numerical Rating Scale (NRS), a ≥ 3-point improvement in eczema-related sleep interference (sleep) NRS, a ≥ 4-point improvement in Dermatology Life Quality Index (DLQI), and DLQI ≤ 5. Specifically, clinically meaningful responses were defined as EASI-50, a ≥ 3-point improvement in itch NRS, or a ≥ 4-point improvement in DLQI at week 16. Results: Among ECZTRA 1 and 2 patients who did not achieve IGA 0/1 at week 16 without rescue medication, a significantly greater proportion of patients receiving tralokinumab versus placebo achieved EASI-50 (33.0% vs 13.0%), a ≥ 3-point improvement in itch NRS (22.6% vs 9.4%), or a ≥ 4-point improvement in DLQI (41.2% vs 24.5%) at week 16. In addition, compared with placebo, a numerically greater proportion of tralokinumab-treated patients achieved all three measures of clinically meaningful response (30% vs 18%) or a clinically meaningful change in at least one outcome (48.8% vs 28.5%). Significantly greater proportions of patients receiving tralokinumab versus placebo achieved additional clinician-reported and patient-reported outcomes, such as EASI-75 (13.5% vs 4.1%), EASI-90 (3.5% vs 1.1%), DLQI ≤ 5 (22.5% vs 12.5%), and a ≥ 3-point improvement in sleep NRS (24.5% vs 11.5%). Conclusions: Tralokinumab provided clinically meaningful responses in patients with moderate-to-severe atopic dermatitis who did not achieve IGA 0/1 at week 16 and/or used rescue medication. Using multiple validated outcome measures of both efficacy and quality of life, alongside IGA scores, can better characterize tralokinumab treatment responses in patients with moderate-to-severe atopic dermatitis. [Video abstract available] Clinical Trial Registration: NCT03131648 (ECZTRA 1); study start date: 30 May, 2017; primary completion date: 7 August, 2018; study completion date: 10 October, 2019. NCT03160885 (ECZTRA 2); study start date: 12 June, 2017; primary completion date: 4 September, 2019; study completion date: 14 August, 2019. [MediaObject not available: see fulltext.]

The patient-reported disease burden in adults with atopic dermatitis : a cross-sectional study in Europe and Canada

Cross-sectional data on patient burden in adults with atopic dermatitis () from real-world clinical practice are limited. This study compared patient-reported burden associated with adult across severity levels from clinical practices in Canada and Europe. This study included adults (18-65 years) diagnosed with by dermatologists, general practitioners or allergists. Participants categorized as mild (n = 547; 37.3%), moderate (n = 520; 35.4%) or severe (n = 400; 27.3%) based on Investigator's Global Assessment completed a questionnaire that included pruritus and pain numerical rating scales, Patient-Oriented-Scoring of Atopic Dermatitis (PO-SCORAD) itch and sleep visual analogue scales, Dermatology Life Quality Index (), and the Hospital Anxiety and Depression Scale (HADS). Participants were also stratified by inadequate efficacy/intolerance/contraindication to cyclosporine [Cyclo; n = 62 (4 mild, 18 moderate, 40 severe)] and any systemic immunomodulatory agent [; n = 104 (13 mild, 31 moderate, 60 severe)] and compared with the severe group excluding participants identified as Cyclo/. Age was similar across severity groups; the proportion of women was higher in the mild group relative to severe (61.2% vs. 50.5%; P < 0.001). Compared with moderate and mild, participants with severe had more comorbidities, higher itch and pain severity, worse sleep and higher levels of anxiety and depression (all P < 0.001). Mean ± score among participants with severe (16.2 ± 6.9) showed a large effect on quality of life that was higher than those with moderate (10.2 ± 6.3) and mild (5.5 ± 4.9) (both P < 0.001). The burden among Cyclo and subgroups was generally similar to that of participants with severe . Adults with reported a substantial burden across multiple domains that was significantly higher in those with severe disease. The burden among participants in the Cyclo/ subgroups was similar to those with severe

Infections in Dupilumab Clinical Trials in Atopic Dermatitis : A Comprehensive Pooled Analysis

Background: Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. Objective: The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. Methods: This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. Results: Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p < 0.01). Systemic anti-infective medication use was lower with dupilumab. Conclusions: Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. ClinicalTrials.gov Identifiers: NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649

Treat-to-target strategies in rheumatoid arthritis: a systematic review and cost-effectiveness analysis

To systematically review clinical and health economic impacts of treat-to-target (TTT) strategies in patients with rheumatoid arthritis (RA) managed in specialist units, compared with routine care. Sixteen and seven electronic databases were searched for clinical RCTs and cost-effectiveness respectively. Study selection, data extraction and quality assessment (Cochrane Collaboration risk of bias criteria) were performed. Evidence was reported by (1) TTT vs. usual care; (2) comparison of different treatment protocols against each other; (3) comparison of different targets against each other. Narrative synthesis was undertaken and conclusions drawn on a trial by trial basis, due to study heterogeneity. Twenty-two RCTs were included. Sixteen were at high risk of bias, five unclear and one low risk. Three trials showed TTT to be more effective than usual care in terms of remissions, in some or all comparisons, whereas one other trial reported no significant difference. Two trials showed TTT to be more effective than usual care in terms of low disease activity (LDA), in some or all comparisons, whereas two trials reported little difference. Some evidence suggests that TTT strategies involving combination therapy can achieve more remissions than those involving monotherapy, but little impact of alternative treatment targets on remission or LDA. Overall, there is evidence that TTT increases remissions in early RA and mixed early and established RA populations, and increases LDA in established RA. Although results varied, typically TTT was estimated to be more cost-effective than usual care. No target appears more effective than others