Pyoderma gangrenosum (PG) is a debilitating inflammatory skin condition characterized by painful, necrotic ulcers, significantly impairing patient quality of life. The variability in clinical outcomes and the lack of standardized treatment protocols challenge effective PG clinical management and research. The Understanding Pyoderma Gangrenosum, Review and Assessment of Disease Effects (UPGRADE) project seeks to address this gap by establishing a core outcome set (COS) for PG clinical trials. UPGRADE has reached consensus on three core outcome domains: Pain, Quality of Life, and Clinical Signs. Here we describe a protocol detailing the next steps of UPGRADE’s COS development to employ an international multistakeholder modified Delphi consensus process to reach consensus on the content of each core domain through the identification and definition of core domain-specific domain items. The process outlined in this protocol will involve generating domain items from the existing literature, refining these items through iterative e-Delphi surveys, and finalizing them in a consensus meeting. This work will enhance the granularity of these domains and facilitate more precise outcome measurement in clinical trials. The development of these detailed domain items is crucial for standardizing outcome reporting across PG trials, thereby improving research quality and enabling better treatment strategies, ultimately enhancing patient outcomes.

BACKGROUND:The Harmonising Outcome Measures for Eczema (HOME) initiative has agreed upon the Core Outcome Set (COS) for use in atopic dermatitis (AD) clinical trials, but additional guidance is needed to maximize its uptake. OBJECTIVES:To provide answers to some of the commonly asked questions about using the HOME COS; to provide data to help with the interpretation of trial results; and to support sample size calculations for future trials. METHODS AND RESULTS:We provide practical guidance on the use of the HOME COS for investigators planning clinical trials in patients with AD. It answers some of the common questions about using the HOME COS, how to access the outcome measurement instruments, what training/resources are needed to use them appropriately and clarifies when the COS is applicable. We also provide exemplar data to inform sample size calculations for eczema trials and encourage standardized data collection and reporting of the COS. CONCLUSIONS:By encouraging adoption of the COS and facilitating consistent reporting of outcome data, it is hoped that the results of eczema trials will be more comprehensive and readily combined in meta-analyses and that patient care will subsequently be improved.

ImportanceOutcome measurement is an essential component of value-based health care and can aid patient care, quality improvement, and clinical effectiveness evidence generation. The Harmonising Outcome Measures for Eczema Clinical Practice initiative aims to identify a list of validated, feasible, outcome measurement instruments recommended to measure atopic dermatitis (AD) in the clinical practice setting. The clinical practice set is a list of instruments that clinicians can pick and choose from to suit their needs in the context of clinical care.ObjectiveTo recommend instruments to measure clinical signs of AD in clinical practice.Evidence ReviewFollowing the predefined roadmap, a mixed methods design was implemented and incorporated systematic reviews and qualitative consensus methods. Previous systematic reviews identified few clinical signs instruments with sufficient validation for recommendation. An updated systematic review evaluating the validity of clinical signs instruments informed an international meeting to reach consensus on recommended instruments to measure AD clinical signs in clinical practice. Consensus was defined as less than 30% disagreement. An in-person consensus exercise was held in Montreal, Canada, on October 16, 2022. The 34 attendees included patient and patient advocate research partners, health care professionals, researchers, methodologists, and industry representatives.FindingsThe updated systematic review found that the Eczema Area and Severity Index (EASI), Scoring Atopic Dermatitis, and objective Scoring Atopic Dermatitis were the only instruments that demonstrated sufficient performance in all assessed measurement properties. The modified EASI and Signs Global Assessment × Body Surface Area instruments were also recommended. The EASI, Validated Investigator Global Assessment, and Investigator’s Global Assessment multiplied by or measured concurrently with a body surface area measure achieved consensus in criteria and were adopted.Conclusions and RelevanceThis consensus statement by the Harmonising Outcome Measures for Eczema initiative suggests that when assessing and documenting clinical signs of AD, there are several valid and feasible instruments that can best fit a clinician’s specific practice needs. These instruments should improve and standardize the documentation of signs severity, help determine the effect of treatment, facilitate the generation of clinical effectiveness evidence, and enhance the implementation of value-based health care.

Background Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with no current standardized outcomes or outcome measures. With a rich investigational therapeutic pipeline, standardization of outcomes and improvement of data quality and interpretability will promote the appropriate and consistent evaluation of potential new therapies. Core outcome sets (COS) are agreed, standardized sets of outcomes that represent the minimum that should be measured and reported in all clinical trials of a specific condition. Objectives To identify and reach a consensus on which domains (what to be measured) should be included in the Understanding Pyoderma Gangrenosum: Review and Analysis of Disease Effects (UPGRADE) core domain set for clinical trials in PG. Methods Collaborative discussions between patients and PG experts, and a systematic review of the literature identified items and prospective domains. A three-round international eDelphi exercise was performed to prioritize the domains and refine the provisional items (consensus: ≥ 70% of participants rating a domain as ‘extremely important’ and < 15% of participants voting ‘not important’), followed by an international meeting to reach consensus on the core domain set (consensus: < 30% disagreement). Item-generation discussions and consensus meetings were hosted via online videoconferences. The eDelphi exercise and consensus voting were performed using Qualtrics survey software. Participants were adults with PG, healthcare professionals, researchers and industry representatives. Results Collaborative discussions and systematic reviews yielded 115 items, which were distilled into 15 prospective domains. The eDelphi exercise removed the three lowest-priority domains (‘laboratory tests’, ‘treatment costs’ and ‘disease impact on family’) and ranked ‘pain’, ‘quality of life’ and ‘physical symptoms’ as the highest-priority prospective domains. Consensus was reached on the domains of ‘pain’, ‘quality of life’ and ‘clinical signs’. The domain of ‘disease course/disease progression’ narrowly failed to reach consensus for inclusion in the core set (32% of participants voted ‘no’). Refinement of this domain definition will be required and presented for consideration at future consensus meetings. Conclusions The UPGRADE core domain set for clinical trials in PG has been agreed by international multistakeholder consensus. Future work will develop and/or select outcome measurement instruments for these domains to establish a COS.

Background: Atopic dermatitis is a common chronic, relapsing, and remitting inflammatory skin disorder associated with cutaneous dysbiosis. Current treatment options often fail to adequately control the disease and have unfavorable safety profiles. There is a need for new options that address these treatment shortcomings. Objective: The aim of the study was to evaluate the efficacy, safety, and tolerability of FB-401, a live therapeutic product of 3 strains of Roseomonas mucosa, compared to matching placebo applied topically 3 times per week to participants ages ≥2 years of age with mild-to-moderate atopic dermatitis. Methods: A randomized, double-blind, placebo-controlled, parallel-group study was conducted. The primary outcome was the proportion of participants with 50% improvement in Eczema Area and Severity Index score from baseline at week 16. 154 subjects aged 2 or older with a clinical diagnosis of atopic dermatitis as defined by Hanifin and Rajka criteria with mild or moderate severity were randomized 1:1 via interactive web response system to FB-401 or placebo. Results: The proportion of subjects who achieved the primary outcome was similar between both treatment groups, with no significant treatment group differences observed at any post-baseline visit. The number of treatment-emergent adverse events and the number of subjects with at least one were similar across treatment groups. One serious adverse event not related to treatment was reported. No treatment-emergent adverse events led to treatment discontinuation or study discontinuation. Conclusions: FB-401 showed an acceptable safety profile but failed to prove superior to placebo in treating children and adults with mild-to-moderate atopic dermatitis.

BACKGROUND:Core outcome sets (COS) are consensus-driven sets of minimum outcomes that should be measured and reported in all clinical trials. COS aim to reduce heterogeneity in outcome measurement and reporting, and selective outcome reporting. Implementing COS into clinical trials is challenging. Guidance to improve COS uptake in dermatology is lacking.OBJECTIVES:To develop a structured practical guide to COS implementation.METHODS:Members of the Harmonising Outcome Measurement for Eczema (HOME) executive committee developed an expert opinion-based roadmap founded on a combination of a review of the COS implementation literature, the Core Outcome Measures in Effectiveness Trials (COMET) initiative resources, input from HOME members and experience in COS development and clinical trials.RESULTS:The data review and input from HOME members was synthesized into themes, which guided roadmap development: (a) barriers and facilitators to COS uptake based on stakeholder awareness/engagement and COS features; and (b) key implementation science principles (assessment-driven, data-centred, priority-based and context-sensitive). The HOME implementation roadmap follows three stages. Firstly, the COS uptake scope and goals need to be defined. Secondly, during COS development, preparation for future implementation is supported by establishing the COS as a credible evidence-informed consensus by applying robust COS development methodology, engaging multiple stakeholders, fostering sustained and global engagement, emphasizing COS ease of use and universal applicability, and providing recommendations on COS use. Thirdly, incorporating completed COS into primary (trials) and secondary (reviews) research is an iterative process starting with mapping COS uptake and stakeholders' attitudes, followed by designing and carrying out targeted implementation projects. Main themes for implementation projects identified at HOME are stakeholder awareness/engagement; universal applicability for different populations; and improving ease-of-use by reducing administrative and study burden. Formal implementation frameworks can be used to identify implementation barriers/facilitators and to design implementation strategies. The effect of these strategies on uptake should be evaluated and implementation plans adjusted accordingly.CONCLUSIONS:COS can improve the quality and applicability of research and, so, clinical practice but can only succeed if used and reported consistently. The HOME implementation roadmap is an extension of the original HOME roadmap for COS development and provides a pragmatic framework to develop COS implementation strategies.

Eczema clinical trials (eCTs) are increasing in number yet little is known about the association between participant demographics and their views on barriers and facilitators of clinical trial participation. Qualitative thematic analysis was performed on open-ended questions from a 46-question online survey that collected information on respondent demographics, understanding of and experience with eCTs, as well as drivers for and barriers to clinical trial participation. Analysis included 924 respondents, 728 (78.8%) adults with eczema and 196 (21.2%) parents/primary caregivers of children (age 0-17) with eczema. Most common theme for motivation to consider eCTs was burden of disease (81.0%); for motivation to explore eCTs in future was burden of disease (57.3%); for reasons why never participated was awareness (57.7%). Respondents ages 65+ significantly cited eligibility as a barrier to trial participation (p = 0.012). A significant association between gender and motivation to consider eCTs was also found (p=0.008). Female participants cited more altruistic reasons for considering eCTs than males and cited disease burden less often. Caregivers cited mitigation of fear/risks/unknowns of trials more than patients when describing what would make them explore eCTs (p=0.034). While not significant, non-Hispanic Asian cited fear/risks/unknowns of eCTs and awareness more and eligibility less than other racial/ethnic groups. Non-Hispanic Black cited awareness in higher proportions for their group as reasons for why they never participated. Improving awareness and addressing patient fears may be an important method in minimizing barriers to participation for people of color and caregivers of pediatric patients interested in eCT participation.

Background:Eczema clinical trials (CTs) are increasing in number, yet participation across the eczema community is low. Little is known about patient characteristics and views on motivators and barriers to CT participation (CTP). Objectives:Determine factors that motivate or impede participation in eczema CT and respondent characteristics associated with these factors. Methods:Qualitative thematic analysis was performed on open-ended questions from an online survey that collected respondent demographics, understanding of and experience with CTs, and drivers/barriers to CTP. Mixed-methods analysis included 924 respondents, 728 (78.8%) adults with eczema and 196 (21.2%) caregivers of children with eczema. Results:A large proportion (71.8%) of respondents would potentially participate in CTs. The most common theme for why a respondent considered or would explore CTP was burden of disease (81.0% and 57.3% respectively). Among those who participated in or considered a CT, caregivers (p = 0.001) reported fewer altruistic motivations compared to adult patients, with trends towards men citing disease burden more (57.0% vs. 50.9%) and altruism less (14.5% vs. 19.2%) than women. Lack of awareness (57.7%) was the most common reason for never having considered a CT. Among those who never considered CTP, age (p = 0.012) and eczema severity at its worst (p = 0.002) were associated with reasons why they never participated. Specifically, older and less severe patients had greater perceptions of eligibility as a barrier to CTP. Caregivers more commonly cited fear of CT risks (20% vs. 11.4%) compared to adult patients who cited accessibility concerns (17.7% vs. 8.6%) as barriers to CT exploration. A subgroup of respondents that never considered CTP and extremely unlikely to consider CTs cited more fears/risks/unknowns and accessibility barriers to CTP. No significant differences in motivators or barriers were observed across race/ethnic groups and urban/rural populations. Conclusions:Motivating factors for CTP include greater disease burden; lack of awareness represents a large barrier. Healthcare providers are trusted intermediaries with ability to refer and inform about CTs; they have a potentially significant role in raising awareness and discussing eczema patient/caregiver perspectives related to CTP. Investigators should tailor recruitment approaches and study design where possible to address identified motivators and barriers.

Pyoderma gangrenosum (PG) is a rare inflammatory condition with an immense disease burden that remains understudied. With limited approved treatments and low-quality clinical evidence, PG continues to have poor patient outcomes. Unfortunately, improvement in PG treatments and patient care is based on additional research endeavors that can only be developed from existing high-quality data. The following protocol outlines the development of the Minimum Data Set for Treatment Effectiveness in Pyoderma gangrenosum (MIDSTEP), a core set of domains and domain items for the Pyoderma Gangrenosum Treatment Effectiveness (PyGaTE) international registry. The outcomes and benefits are focused on providing real-world data for physicians to improve their clinical decisions on PG treatment and inform clinical trial design, promoting clinical research among the international scientific community. MIDSTEP is a multi-phase project. The first phase will produce a domain item list from a literature review to take into the second phase which would finalize the core data set by an e-Delphi exercise. There will be a single stakeholder group participating together in the e-Delphi consisting of PG experts (healthcare providers, researchers, methodologists, industry representatives, and regulators), ulcerative PG patients, and PG patient advocates. The methodology outlined in the protocol is a systematic method based on several guidelines through COMET and established dermatologic registries and outcome sets with systematic methodologies of their own. The third phase will identify the instruments for the items, the 'when to measure' the items, and the platform for the registry. The last phase is the implementation and continued maintenance of the international registry PyGaTE. By solidifying a consensus on standardized outcomes and collecting information on PG treatment effectiveness in a centralized database, existing treatments can be compared more systematically and analyzed with increased evidence. MIDSTEP and the PyGaTE international registry will have the ambitious goal to generate and disseminate real-world data that can be used by all stakeholders to improve health outcomes for PG patients. Future potential for the outcome of this project includes the development of a gold-standard PG treatment.

Atopic dermatitis is a chronic inflammatory skin condition that affects approximately 18 million people in the United States. Assessing the extent and severity of atopic dermatitis is critical for determining baseline disease burden and treatment effectiveness for both investigators and clinicians. Considerable efforts over the past several decades have been made in developing a highly validated instrument called the Eczema Area and Severity Index (EASI). Although several guides exist for the EASI, questions continue to arise regarding its use and interpretation. This review was developed to serve as the definitive guide for the EASI and to address commonly asked questions.

Rett syndrome is a neurological disease due to loss-of-function mutations in the transcription factor, Methyl CpG binding protein 2 (MECP2). Because overexpression of endogenous MECP2 also causes disease, we have exploited a targeted RNA-editing approach to repair patient mutations where levels of MECP2 protein will never exceed endogenous levels. Here, we have constructed adeno-associated viruses coexpressing a bioengineered wild-type ADAR2 catalytic domain (Editase wt ) and either Mecp2 -targeting or nontargeting gfp RNA guides. The viruses are introduced systemically into male mice containing a guanosine to adenosine mutation that eliminates MeCP2 protein and causes classic Rett syndrome in humans. We find that in the mutant mice injected with the Mecp2 -targeting virus, the brainstem exhibits the highest RNA-editing frequency compared to other brain regions. The efficiency is sufficient to rescue MeCP2 expression and function in the brainstem of mice expressing the Mecp2 -targeting virus. Correspondingly, we find that abnormal Rett-like respiratory patterns are alleviated, and survival is prolonged, compared to mice injected with the control gfp guide virus. The levels of RNA editing among most brain regions corresponds to the distribution of guide RNA rather than Editase wt . Our results provide evidence that a targeted RNA-editing approach can alleviate a hallmark symptom in a mouse model of human disease.