Summary
Background
The Harmonising Outcome Measures for Eczema (HOME) initiative has defined four core outcome domains for a core outcome set (COS) to be measured in all atopic eczema (AE) trials to ...ensure cross‐trial comparison: clinical signs, symptoms, quality of life and long‐term control.
Objectives
The aim of this paper is to report on the consensus process that was used to select the core instrument to consistently assess symptoms in all future AE trials.
Methods
Following the HOME roadmap, two systematic reviews were performed which identified three instruments that had sufficient evidence of validity, reliability and feasibility to be considered for the final COS.
Results
At the fourth international HOME meeting, there was broad consensus among all stakeholders that the Patient‐Oriented Eczema Measure (POEM) should be used as the core instrument (87·5% agreed, 9·4% unsure, 3·1% disagreed).
Conclusions
All relevant stakeholders are encouraged to use POEM as the chosen instrument to measure the core domain of symptoms in all future AE clinical trials. Other instruments of interest can be used in addition to POEM.
What's already known about this topic?
There is insufficient high‐quality evidence for many of the treatments of atopic eczema (AE), which is partly due to the heterogeneity in outcomes used in clinical trials.
The Harmonising Outcome Measures for Eczema initiative defined ‘symptoms’ as one of the core outcome domains that should be measured in AE clinical trials.
What does this study add?
Consensus was reached on the Patient‐Oriented Eczema Measure (POEM) as the core instrument to measure symptoms.
This statement should promote awareness among all stakeholders.
What are the clinical implications of this work?
Not only itch and sleeplessness are symptoms important for patients with AE.
All relevant stakeholders are encouraged to use POEM as the chosen instrument to measure the core domain of symptoms in all future AE clinical trials.
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Linked Comment: Naldi. Br J Dermatol 2017; 176:852–853
Plain language summary available online
Summary
Background
The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema (AE) clinical trials. Previous consensus meetings have ...agreed on preferred instruments for clinician‐reported signs (Eczema Area and Severity Index, EASI) and patient‐reported symptoms (Patient‐Oriented Eczema Measure, POEM). This paper reports consensus decisions from the HOME VII meeting.
Objectives
To complete the core outcome set for AE by agreeing on core outcome instruments for the domains of quality of life (QoL), long‐term control and itch intensity.
Methods
A face‐to‐face consensus meeting was held in Tokyo, Japan (8–10 April 2019) including 75 participants (49 healthcare professionals/methodologists, 14 patients, 12 industry representatives) from 16 countries. Consensus decisions were made by presentations of evidence, followed by whole and small group discussions and anonymous voting using predefined consensus rules.
Results
It was agreed by consensus that QoL should be measured using the Dermatology Life Quality Index (DLQI) for adults, the Children’s Dermatology Life Quality Index (CDLQI) for children and the Infant’s Dermatology Quality of Life Index (IDQoL) for infants. For long‐term control, the Recap of Atopic Eczema (RECAP) instrument or the Atopic Dermatitis Control Test (ADCT) should be used. Consensus was not reached over the frequency of data collection for long‐term control. The peak itch numerical rating scale (NRS)‐11 past 24 h was recommended as an additional instrument for the symptom domain in trials of older children and adults. Agreement was reached that all core outcome instruments should be captured at baseline and at the time of primary outcome assessment as a minimum.
Conclusions
For now, the core outcome set for clinical trials in AE is complete. The specified domains and instruments should be used in all new clinical trials and systematic reviews of eczema treatments.
What is already known about this topic?
Core outcomes sets improve the design and reporting of clinical trials, reduce selective outcome reporting bias and facilitate meta‐analysis of results in systematic reviews.
The HOME core outcome set for eczema recommends the inclusion of four core domains in all atopic eczema trials: clinician‐reported signs, patient‐reported symptoms, health‐related quality of life (HrQoL) and long‐term control.
Clinician‐reported signs should be captured using the Eczema Area and Severity Index (EASI) and patient‐reported symptoms using the Patient‐Oriented Eczema Measure (POEM).
What does this study add?
The HOME core outcome set is now complete and recommended core outcome instruments have been agreed on for all four domains.
Core outcome instruments for HrQoL: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children and Infant’s Dermatology Quality of Life Index (IDQoL) for infants.
Core outcome instruments for long‐term control: either the Recap of Atopic Eczema (RECAP) or the Atopic Dermatitis Control Test (ADCT).
In addition, itch intensity should be measured using the peak NRS‐11 past 24 h for trials including older children and adults.
What are the clinical implications of this work?
If all future trials of eczema treatments include the HOME core outcome instruments, then trial results will be more readily incorporated into meta‐analyses in systematic reviews and clinical care will be informed by the best available evidence.
Linked Comment: D.F. Murrell and C.F. Paul. Br J Dermatol 2021; 185:13–14.
Summary
Background
Dupilumab is the first biologic registered for the treatment of moderate‐to‐severe atopic dermatitis (AD), and efficacy was shown in phase III clinical trials (primary outcome at ...week 16 was reached in 38% of patients). Currently, there are limited daily practice data available for dupilumab, especially when it is combined with systemic immunosuppressants.
Objectives
To evaluate dupilumab treatment in daily practice in patients with AD.
Methods
In this observational cohort study, we prospectively included all adult patients with AD who had been treated with dupilumab in two university hospitals in the Netherlands. Concomitant systemic immunosuppressive treatment was monitored. Physician‐reported outcome measures and patient‐reported outcome measures (PROMs) after ≥ 12 weeks of follow‐up were analysed. We used a linear mixed‐effects model to determine changes in scores during follow‐up.
Results
Ninety‐five patients were included. Of these, 62 patients were using systemic immunosuppressants at baseline; the use of systemic immunosuppressants was continued during dupilumab treatment in 43 patients. From baseline to 16 weeks of treatment, the estimated mean Eczema Area and Severity Index score (0–72) decreased from 18·6 95% confidence interval (CI) 16·0–21·4) to 7·3 (95% CI 5·4–10·0), and the estimated mean PROMs showed a decrease of 41–66%. Investigator's Global Assessment 0 or 1 (clear/almost clear) was reached in 38% of the patients. Five patients discontinued dupilumab treatment due to side‐effects or ineffectiveness. Eye symptoms and orofacial (nonocular) herpes simplex virus (HSV) reactivation were reported in 62% and 8% of the patients, respectively.
Conclusions
Dupilumab treatment in daily practice shows a clinically relevant improvement of physician‐reported outcome measures and PROMs, which is in line with efficacy data from clinical trials. Besides frequently reported eye symptoms and orofacial (nonocular) HSV reactivation, there were no apparent safety concerns.
What's already known about this topic?
Dupilumab has been shown to be an efficacious treatment for atopic dermatitis in several clinical trials.
However, it is known that there may be considerable differences in patient characteristics and treatment responses between clinical trials and daily practice.
What does this study add?
This study presents the first experience with dupilumab treatment in 95 patients with atopic dermatitis in daily practice in two Dutch university hospitals.
Less stringent inclusion and exclusion criteria and follow‐up schedules, in contrast to those used in clinical trials, might better represent daily practice.
Dupilumab treatment shows a clinically relevant improvement of physician‐ and patient‐reported outcome measures; besides patient‐reported eye symptoms (in 59 of 95 patients; 62%) and an apparent increase in orofacial (nonocular) herpes simplex virus reactivation (eight of 95 patients; 8%), there were no other safety concerns during follow‐up up to 16 weeks of dupilumab treatment.
Linked Comment: Deleuran and Vestergaard. Br J Dermatol 2020; 182:275–276.
Plain language summary available online
Background
Symptoms have been identified as a core outcome domain for atopic eczema (AE) trials. Various instruments exist to measure symptoms in AE, but they vary in quality and there is a lack of ...standardization between clinical trials. Our objective was to systematically evaluate the quality of the evidence on the measurement properties of AE symptom instruments, thereby informing consensus discussions within the Harmonising Outcome Measures for Eczema (HOME) initiative regarding the most appropriate instruments for the core outcome domain symptoms.
Methods
Using the COnsensus‐based Standards for the selection of health Measurement INstruments (COSMIN) checklist and predefined criteria for good measurement properties on identified development and validation studies of AE symptom instruments, a best evidence synthesis was performed to draw an overall conclusion on quality of the instruments and to provide recommendations.
Results
Eighteen instruments were identified and evaluated. When the quality and results of the studies were considered, only five of these instruments had sufficient validation data to consider them for the core outcome set for the core outcome domain symptoms. These were the paediatric Itch Severity Scale (ISS), Patient‐Oriented Eczema Measure (POEM), Patient‐Oriented SCOring Atopic Dermatitis (PO‐SCORAD), Self‐Administered Eczema Area and Severity Index (SA‐EASI) and adapted SA‐EASI.
Conclusions
ISS (paediatric version), POEM, PO‐SCORAD, SA‐EASI and adapted SA‐EASI are currently the most appropriate instruments and therefore have the potential to be recommended as core symptom instrument in future clinical trials. These findings will be utilized for the development of a core outcome set for AE.
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.
Summary
‘Symptoms’ is a core outcome domain for atopic eczema (AE) trials, agreed by consensus as part of the Harmonising Outcome Measures for Eczema (HOME) initiative. To standardize and validate ...the core domain symptoms and symptom instruments for AE trials the HOME roadmap is followed. Its first step is to establish if and how symptoms have been measured in published AE treatment trials. Therefore the Global Resource for Eczema Trials database was used to collect all randomized controlled trials (RCTs) of treatments for AE between January 2000 and April 2014. Study selection and data extraction were performed by three reviewers independently. We identified the use of symptoms in 295 of 378 trials (78%). Symptoms as a primary end point were applied by 147 RCTs (50%). Seventeen different symptoms were measured, but mostly itch and sleep loss. Symptoms were assessed by only 37% of trials by a stand‐alone symptom measurement. Overall 63% of RCTs used a composite instrument, and 30 different instruments were identified. The Scoring Atopic Dermatitis (SCORAD) index was the most commonly applied, but only 23% of RCTs reported the SCORAD symptom score separately. This systematic review demonstrates that symptoms, most frequently itch and sleep loss, are commonly reported in AE treatment trials, but are measured using many different instruments. Often symptoms are evaluated as part of a composite instrument, and currently it is not possible to extract symptoms‐only data from most published studies. Future trials should report symptom scores to permit meta‐analysis of the core outcomes.
What's already known about this topic?
There is a high level of variation in outcome domains and instruments used for atopic eczema (AE).
Harmonization of AE instruments is necessary to allow better evidence‐based clinical decision making.
The Harmonising Outcome Measures for Eczema (HOME) initiative aims to validate a core outcome set (COS) for AE clinical trials; ‘symptoms’ is selected as one of the four core outcome domains beside clinical signs, quality of life and long‐term control.
What does this study add?
Symptoms, most frequently itch and sleep loss, are commonly reported in AE trials, but are often poorly measured using many different instruments and as part of a composite instrument, most commonly the SCORing Atopic Dermatitis (SCORAD) index.
Describing patient‐reported symptoms and clinician‐reported signs separately will improve trial reporting and facilitate meta‐analysis.
Deployment of the COS for AE in future trials is a key requirement in moving forward.
Linked Comment: Fedorowicz and van Zuuren. Br J Dermatol 2016; 175:667–668.
Summary
Background
For many years dermatologists have had access to few therapies for patients with moderate‐to‐severe atopic eczema (AE). New promising therapies are entering the market but ...conventional phototherapies and systemic therapies have more well‐known safety profiles, lower costs and wider availability.
Objectives
To provide insight into current prescribing practices of conventional phototherapy and systemic immunomodulatory therapies for adults with chronic AE, and the factors influencing these prescribing practices, before biologics and other novel therapeutics become routine clinical practice.
Methods
In this exploratory study dermatologists were invited to participate in an online survey via a mailing list of the European Academy of Dermatology and Venereology and national societies. Data were collected on participant characteristics (including clinical practice data), the use of phototherapies and systemic therapies, and factors influencing their use.
Results
From 30 European countries, 238 out of 361 dermatologists willing to participate (65·9%) completed the survey, with 229 meeting the inclusion criteria. For phototherapy (prescribed by 84·7%), most preferred narrowband ultraviolet B as first line (80·9%) and psoralen plus ultraviolet A as second (21·6%). For systemic therapy (prescribed by 95·2%) ciclosporin (54·1%), oral corticosteroids (32·6%) and methotrexate (30·7%) were used first line. Dermatologists relied mostly on personal experience for prescribing phototherapy and systemic therapy. Azathioprine and mycophenolic acid were prescribed by only 135 (59·0%) and 85 (37·1%) participants in total, mostly due to a lack of personal experience.
Conclusions
This study provides insight into prescribing practices for conventional phototherapy and systemic therapy in Europe and shows that off‐label therapies are also preferred as first‐line choice of systemic therapy.
What is already known about this topic?
Varying prescribing practices were found for adult (in the UK) and paediatric (in Northern America and Europe) patients with moderate‐to-severe atopic eczema (AE).
Not much is known about the prescription of phototherapy and (off‐label) systemic therapy for adult patients in Europe.
Although therapies like dupilumab are promising new treatment modalities, better‐known safety profiles, lower costs and better availability are reasons to improve the evidence profile of conventional systemic therapies like ciclosporin.
What does this study add?
Prescribing practices of European dermatologists treating adult patients with moderate‐to-severe AE show diversity.
Most dermatologists prefer narrowband ultraviolet B as first‐line phototherapy, followed by psoralen plus ultraviolet A as second line.
Next to ciclosporin, which is most commonly prescribed, (off‐label) methotrexate and oral corticosteroids are also frequently used as first‐line systemic agents in chronic AE.
Lack of personal experience with azathioprine and mycophenolic acid was the most important reason against their prescription.
What are the clinical implications of the work?
The results from this study might help to improve the experience with, and prescribing of, all available conventional phototherapies and (off‐label) systemic therapies.
Guidelines developers might use these results to develop and implement treatment algorithms.
Linked Comment: Bruin‐Weller. Br J Dermatol 2020; 183:987–988.
Plain language summary available online
Summary
Background
Systemic treatment is indicated for moderate‐to‐severe atopic dermatitis (AD) refractory to topical treatment. Long‐term evidence, up to 5 years, of off‐label prescribed ...methotrexate (MTX) and azathioprine (AZA) is lacking.
Objectives
To investigate long‐term effectiveness, safety and drug survival of MTX and AZA.
Methods
In an open‐label follow‐up phase of a clinical trial, patients were seen every 3 months for 5 years. MTX and AZA doses could be increased or decreased concurrent with daily clinical practice. Primary effectiveness outcomes were mean absolute and relative reduction in SCORing Atopic Dermatitis (SCORAD) index and Investigator's Global Assessment (IGA) after 5 years compared with baseline. To assess safety, the type, frequency, severity and relatedness to treatment of adverse events were investigated. Drug survival was analysed by Kaplan–Meier curves.
Results
Thirty‐five of 43 originally included patients participated, of whom 27 completed the follow‐up. At year 5, the mean relative reduction in SCORAD index was similar in the MTX and AZA groups: 53% and 54% using descriptive analysis. Twelve serious adverse events occurred in 5 years; for three there was a possible causal relationship. Drug survival demonstrated a longer survival for MTX, but survival in both groups was low after 5 years (MTXn = 5, AZAn = 1).
Conclusions
Based on this relatively small pragmatic study, MTX and AZA seem to be effective and safe as maintenance treatments in moderate‐to‐severe AD up to 5 years. Few patients in both groups survive on their originally allocated drug although some discontinued because of controlled AD.
What's already known about this topic?
Azathioprine (AZA) and methotrexate (MTX) seem to be effective and safe drugs in the short term for adults with severe atopic dermatitis (AD) based on a small body of evidence.
The paucity of evidence, especially on long‐term effectiveness and safety, needs to be addressed to inform clinical management.
What does this study add?
This is the first pragmatic study describing the 5‐year effectiveness and safety of MTX and AZA in adults with moderate‐to‐severe AD.
MTX and AZA seem to be effective and safe in the long term.
MTX seems to have a longer drug survival than AZA, but both groups have few survivals at year 5, although some patients discontinued because of controlled AD.
Linked Comment: von Kobyletzki and Svensson. Br J Dermatol 2018; 178:1236–1237.
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Summary
Background
Comparative, real‐life and long‐term evidence on the effectiveness and safety of phototherapy and systemic therapy in moderate‐to‐severe atopic eczema (AE) is limited. Such data ...must come from well‐designed prospective patient registries. Standardization of data collection is needed for direct comparisons and data pooling.
Objectives
To reach a consensus on how and when to measure the previously defined domain items of the TREatment of ATopic eczema (TREAT) Registry Taskforce core dataset for research registries for paediatric and adult patients with AE.
Methods
Proposals for the measurement instruments were based on recommendations of the Harmonising Outcome Measures for Eczema (HOME) initiative, the existing AE database of TREATgermany, systematic reviews of the literature and expert opinions. The proposals were discussed at three face‐to‐face consensus meetings, one teleconference and via e‐mail. The frequency of follow‐up visits was determined by an expert survey.
Results
A total of 16 experts from seven countries participated in the ‘how to measure’ consensus process and 12 external experts were consulted. A consensus was reached for all domain items on how they should be measured by assigning measurement instruments. A minimum follow‐up frequency of initially 4 weeks after commencing treatment, then every 3 months while on treatment and every 6 months while off treatment was defined.
Conclusions
This core dataset for national AE research registries will aid in the comparability and pooling of data across centres and country borders, and enables international collaboration to assess the long‐term effectiveness and safety of phototherapy and systemic therapy used in patients with AE.
What's already known about this topic?
Comparable, real‐life and long‐term data on the effectiveness and safety of phototherapy and systemic therapy in patients with atopic eczema (AE) are needed.
There is a high diversity of outcomes and instruments used in AE research, which require harmonization to enhance comparability and allow data pooling.
What does this study add?
Our taskforce has reached international consensus on how and when to measure core domain items for national AE research registries.
This core dataset is now available for use by researchers worldwide and will aid in the collection of unified data.
What are the clinical implications of this work?
The data collected through this core dataset will help to gain better insights into the long‐term effectiveness and safety of phototherapy and systemic therapy in AE and will provide important information for clinical practice.
Standardization of such data collection at the national level will also allow direct data comparisons and pooling across country borders (e.g. in the analysis of treatment‐related adverse events that require large patient numbers).
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Summary
Background
Evidence of immunomodulatory therapies to guide clinical management of atopic eczema (AE) is scarce, despite frequent and often off‐label use. Patient registries provide valuable ...evidence for the effects of treatments under real‐world conditions that can inform treatment guidelines, give the opportunity for health economic evaluation and the evaluation of quality of care, as well as pharmacogenetic and dynamic research, which cannot be adequately addressed in clinical trials.
Objectives
The TREatment of ATopic eczema (TREAT) Registry Taskforce aims to seek international consensus on a core set of domains and items (‘what to measure’) for AE research registries, using a Delphi approach.
Methods
Participants from six stakeholder groups were included: doctors, nurses, nonclinical researchers, patients, industry and regulatory body representatives. The eDelphi comprised three sequential online rounds, requesting participants to rate the importance of each proposed domain item. Participants could add domain items to the proposed list in round 1. A final consensus meeting was held to ratify the core set.
Results
Participants (n = 479) from 36 countries accessed the eDelphi platform, of whom 86%, 79% and 74% completed rounds 1, 2 and 3, respectively. At the face‐to‐face consensus meeting attended by 42 participants the final core set was established containing 19 domains with 69 domain items (49 baseline and 20 follow‐up items).
Conclusions
This core set of domains and items to be captured by national AE systemic therapy registries will standardize data collection and thereby allow direct comparability across registries and facilitate data pooling between countries. Ultimately, it will provide greater insight into the effectiveness, safety and cost‐effectiveness of photo‐ and systemic immunomodulatory therapies.
What's already known about this topic?
Evidence of photo‐ and systemic immunomodulatory therapies to guide clinical management for atopic eczema (AE) is scarce, despite frequent and often off‐label use.
There is a need to gather long‐term, comparative and real‐life data on the effectiveness, safety and cost‐effectiveness of these therapies beyond the confines of short‐term randomized controlled trials, especially when new biological and small‐molecule therapies are entering clinical practice.
Patient registries can provide valuable data to address these issues.
What does this study add?
By performing an international Delphi exercise, consensus was reached on a core set of domains and items to be captured by national AE patient registries.
This core set will standardize data collection and thereby allow direct comparability across registries and facilitate data pooling between countries.
What are the clinical implications of this work?
Ultimately, this core set will provide greater insight into the effectiveness, safety and cost‐effectiveness of photo‐ and systemic immunomodulatory therapies.
This may fill the current gaps of evidence and lead to new guidelines for daily clinical practice, and thereby may contribute to the improvement of the care of children and adults with AE.
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