The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis
TL;DR: In this paper, the reliability of the EASI scoring system was evaluated by assessing inter-and intra-observer consistency, and the results indicated that the evaluators assessed the patients consistently across both study days.
Abstract: :Objective– To test the reliability of the eczema area and severity index (EASI) scoring system by assessing inter- and intra-observer consistency. Design: Training of evaluators, application, and assessment over 2 consecutive days. Setting– An academic center. Patients– Twenty adults and children with atopic dermatitis (AD); cohort 1 (10 patients ≥8 years) and cohort 2 (10 patients <8 years). Interventions– None. Main outcome measure– The EASI was used by 15 dermatologist evaluators to assess atopic dermatitis in cohort 1 and cohort 2 on 2 consecutive days. Inter- and intraobserver reliability were analyzed. Results– Overall intra-evaluator reliability of the EASI was in the fair-to-good range. Inter-evaluator reliability analyses indicated that the evaluators assessed the patients consistently across both study days. Conclusions– This study demonstrated that the EASI can be learned quickly and utilized reliably in the assessment of severity and extent of AD. There was consistency among the evaluators between consecutive days of evaluation. These results support the use of the EASI in clinical trials of therapeutic agents for AD.
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Oregon Health & Science University1, University of Bonn2, Icahn School of Medicine at Mount Sinai3, University of Rochester4, Regeneron5, University of Sheffield6, Northwestern University7, Aarhus University8, Centre Hospitalier Universitaire de Nice9, University of Tartu10, Charité11, Ludwig Maximilian University of Munich12, Laval University13, Sanofi S.A.14
TL;DR: Dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo in two phase 3 trials of identical design.
Abstract: BackgroundDupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis. MethodsIn two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment and a reduction of 2 points or more in that score from baseline at week 16. ResultsWe enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who...
1,318 citations
TL;DR: Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity, and side-effect profiles were not dose-limiting.
Abstract: BACKGROUND Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)–mediated inflammation could help in the treatment of related diseases, including atopic dermatitis. METHODS We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator’s global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome. RESULTS In the 4-week monotherapy studies, dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator’s global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P = 0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P = 0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with dupilumab. CONCLUSIONS Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not doselimiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.)
1,096 citations
Boston Children's Hospital1, Children's Memorial Hospital2, Wake Forest University3, Oregon Health & Science University4, University of California, San Francisco5, University of British Columbia6, New York University7, Case Western Reserve University8, Mayo Clinic9, University of Pennsylvania10, Northwestern University11, Nottingham University Hospitals NHS Trust12, University of Alabama at Birmingham13, Rafael Advanced Defense Systems14, American Academy of Dermatology15, Seattle Children's16
TL;DR: This guideline addresses important clinical questions that arise in the management and care of AD, providing updated and expanded recommendations based on the available evidence.
Abstract: Atopic dermatitis (AD) is a chronic, pruritic, inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in the management and care of AD, providing updated and expanded recommendations based on the available evidence. In this first of 4 sections, methods for the diagnosis and monitoring of disease, outcomes measures for assessment, and common clinical associations that affect patients with AD are discussed. Known risk factors for the development of disease are also reviewed.
874 citations
TL;DR: It is suggested that an impairment in tight junctions contributes to the barrier dysfunction and immune dysregulation observed in AD subjects and that this may be mediated in part by reductions in claudin-1.
Abstract: Background Atopic dermatitis (AD) is characterized by dry skin and a hyperactive immune response to allergens, 2 cardinal features that are caused in part by epidermal barrier defects. Tight junctions (TJs) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway. Objective We evaluated the expression/function of the TJ protein claudin-1 in epithelium from AD and nonatopic subjects and screened 2 American populations for single nucleotide polymorphisms in the claudin-1 gene (CLDN1). Methods Expression profiles of nonlesional epithelium from patients with extrinsic AD, nonatopic subjects, and patients with psoriasis were generated using Illumina's BeadChips. Dysregulated intercellular proteins were validated by means of tissue staining and quantitative PCR. Bioelectric properties of epithelium were measured in Ussing chambers. Functional relevance of claudin-1 was assessed by using a knockdown approach in primary human keratinocytes. Twenty-seven haplotype-tagging SNPs in CLDN1 were screened in 2 independent populations with AD. Results We observed strikingly reduced expression of the TJ proteins claudin-1 and claudin-23 only in patients with AD, which were validated at the mRNA and protein levels. Claudin-1 expression inversely correlated with T H 2 biomarkers. We observed a remarkable impairment of the bioelectric barrier function in AD epidermis. In vitro we confirmed that silencing claudin-1 expression in human keratinocytes diminishes TJ function while enhancing keratinocyte proliferation. Finally, CLDN1 haplotype-tagging SNPs revealed associations with AD in 2 North American populations. Conclusion Collectively, these data suggest that an impairment in tight junctions contributes to the barrier dysfunction and immune dysregulation observed in AD subjects and that this may be mediated in part by reductions in claudin-1.
529 citations
TL;DR: Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns, and shows that IL-4 and IL-13 are key drivers of atopic skinitis.
469 citations
References
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Book•
01 Jan 1986
TL;DR: The Parallel Groups Design as mentioned in this paper is a special case of the Parallel Groups Study, and it is used to control for prognostic variables in linear regression analysis of linear regressions of linear models.
Abstract: Reliability of Measurement. Simple Linear Regression Analysis. The Parallel Groups Design. Special Cases of the Parallel Groups Study. Blocking to Control for Prognostic Variables. Stratification to Control for Prognostic Variables. Analysis of Covariance and the Study of Change. Repeated Measurements Studies. Latin and Greco-Latin Squares. The Crossover Study. Balanced Incomplete Block Designs. Factorial Experiments. Split-Plot Designs and Confounding. Appendix. Indexes.
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4,445 citations
TL;DR: Ro 10--9359 proved to be an extremely potent antipsoriatic drug and a more than 90% reduction of psoriatic lesions could be seen in 10 patients out of 20 after 4-8 weeks of treatment.
Abstract: Ro 10–9359 is a retinoic acid derivative, selected for study because of a better tolerance than retinoic acid, shown in animal experiments. Doses of 25 mg b.i.d., 25 mg t.i.d. and 50 mg b.i.d. were ad
2,510 citations
TL;DR: Assessment methods for atopic dermatitis are not standardized, and therapeutic studies are difficult to interpret, so consensus on these methods is needed to obtain a consensus on them.
Abstract: Background . Assessment methods for atopic dermatitis (AD) are not standardized, and therapeutic studies are difficult to interpret. Aims . To obtain a consensus on
1,976 citations
TL;DR: The statistics kappa and weighted kappa (Cohen, 1960) were introduced to provide coefficients of agreement between two raters for nominal scales as discussed by the authors, and they were used to provide a measure of the relative seriousness of the different possible disagreements.
Abstract: The statistics kappa (Cohen, 1960) and weighted kappa (Cohen, 1968) were introduced to provide coefficients of agreement between two raters for nominal scales. Kappa is appropriate when all disagreements may be considered equally serious, and weighted kappa is appropriate when the relative seriousness of the different possible disagreements can be specified. The papers describing these two statistics also present expressions for their standard errors. These expressions are incorrect, having been derived from the contradictory assumptions of fixed marginal totals and binomial variation of cell frequencies. Everitt (1968) derived the exact variances of weighted and unweighted kappa when the parameters are zero by assuming a generalized hypergeometric distribution. He found these expressions to be far too complicated for routine use, and offered, as alternatives, expressions derived by assuming binomial distributions. These alternative expressions are incorrect, essentially for the same reason as above. Assume that N subjects are distributed into k* cells by each of them being assigned to one of k categories by one rater and, independently, to one of the same k categories by a second
1,443 citations