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Background: The term 'flare' is used across multiple diseases, including atopic dermatitis (AD), to describe increased disease activity. While several definitions of an AD flare have been proposed, no single definition of AD flare is widely accepted and it is unclear what the term 'AD flare' means from the patient perspective., Objectives: To understand AD flares from the adult patient perspective and to explore how adults with AD define an AD flare., Methods: Participants were adults with AD recruited from the National Eczema Association Ambassadors programme, a volunteer patient-engagement programme. They participated in online focus groups to discuss how they describe AD flares from their perspective, how they define its start and stop, and how they relate to existing definitions of flare. Using a grounded theory approach, transcripts were analysed and coded using an iterative process to identify concepts to support a patient-centred conceptual framework of 'flare'., Results: Six 90-min focus groups of 3-8 participants each were conducted with 29 US adults (≥ 18 years of age) with AD who had at least one self-reported AD flare in the past year. When participants were presented with examples of previously published definitions of AD flare, participants found them problematic and unrelatable. Specifically, they felt that flare is hard to quantify or put on a numerical scale, definitions cannot solely be about skin symptoms and clinical verbiage does not resonate with patients' lived experiences. Concepts identified by patients as important to a definition of flare were changes from patient's baseline/patient's normal, mental/emotional/social consequences, physical changes in skin, attention needed/all-consuming focus, itch-scratch-burn cycle and control/loss of control/quality of life. Figuring out the trigger that initiated a flare was an underlying concept of the experience of flare but was not considered a contributor to the definition., Conclusions: The results highlight the complexity and diversity of AD flare experiences from the adult patient perspective. Previously published definitions of AD flares did not resonate with patients, suggesting a need for a patient-centred flare definition to support care conversations and AD management., Competing Interests: Conflicts of interest W.S.B. reports sponsorship from Sanofi/Regeneron paid to her institution during the conduct of the study; advisory board honoraria paid to her institution from Pfizer and Amgen; and research grants from Pfizer. A.M.D. has received compensation from the British Journal of Dermatology (reviewer and Section Editor), American Academy of Dermatology (guidelines writer), National Eczema Association (NEA; grant reviewer), Canadian Dermatology Today (manuscript writer) and Canadian Agency for Drugs and Technologies in Health ­(consultant). He has received research grants to his institution from the NEA, the Eczema Society of Canada, the Canadian Dermatology Foundation, the Canadian Institutes for Health Research, the US National Institutes of Health and the Physicians Services Incorporated Foundation. K.N.D. and A.M.D. received research funding paid to their institutions from the NEA for the conduct of the research reported in this manuscript. I.J.C.T., K.A. and M.W. declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Importance: Atopic dermatitis (AD) is associated with psychosocial symptoms, resulting in significant mental health burden and reduced quality of life., Objective: To understand mental health support received by patients from their primary eczema provider., Design: We administered a cross-sectional survey ( N  = 954) to US caregivers and adult patients with AD., Setting: The National Eczema Association (United States) conducted an online survey in October 2022 among self-selected patients and caregivers., Outcome: Patients and caregivers of AD patients reported on mental health conversations and types of mental health support received by their/their child's provider., Results: Many patients did not discuss (41.9%) or were not asked (50.5%) about their mental health by their eczema provider, and 64% reported not receiving a mental health referral. Patients were more likely to receive mental health support if they were male (2.00 [1.08-3.69]), low or middle education level (4.89 [2.10-11.36], 2.71 [1.36-5.40]), or had purchased insurance policies (4.43 [1.79-10.98]). Providers were most likely to refer patients to counseling services (22.5%), followed by alternative mental health therapy (14.9%), cognitive behavioural therapy (13.3%) and peer/social support groups (12.2%)., Conclusion: Despite the strong association between AD and mental health conditions, there is a significant proportion of patients that report not receiving mental health support from their/their child's primary eczema provider. Screening with validated measures may improve the identification of patients requiring additional support. Future research should evaluate the efficacy of mental health resources and barriers to accessing and referring patients for mental health care., Competing Interests: This study was sponsored by the National Eczema Association (NEA). JKJ, AL, and WSB are employees of the NEA. WSB received advisory board honoraria from Pfizer and Incyte, and research grants from Pfizer., (© 2024 The Author(s). Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Competing Interests: Conflicts of interest Dr Brandling-Bennett has served as principal investigator for Lilly. Dr Arkin has received consulting fees from AbbVie, Regeneron, and Verrica. Dr Hebert has received research grants (paid to UTHealth McGovern Medical School) from LEO Pharma, Mayne Pharma, UCB, GSK, Ortho Dermatolgics, Amgen, Arcutis, AbbVie, and Pfizer; has received honoraria from Pfizer, Arcutis, UCB, Verrica, LEO Pharma, Novan, Incyte, Janssen, Mayne Pharma, and Castle Creek Bioscience; and has served on drug safety monitoring boards for Ortho Dermatologics, GSK, and Sanofi Regeneron. Dr Cordoro has served as a member of a scientific steering committee for Celgene. Dr Curran has served as an advisory board member for Novartis, receiving honoraria. Dr Dalrymple has served as an advisory board member for Novartis. Dr Flohr is chief investigator of the UK National Institute for Health Research-funded TREAT (ISRCTN15837754, EudraCT 2,015-002,013-29) and SOFTER (Clinicaltrials.gov: NCT03270566) trials as well as the UK-Irish Atopic Eczema Systemic Therapy Register (A-STAR; ISRCTN11210918) and a principal investigator in the European Union (EU) Horizon 2020-funded BIOMAP Consortium (http://www.biomap-imi.eu/). He also leads the EU Trans-Foods Consortium. His department has received funding from Sanofi-Genzyme and Pfizer for host-microbiome research. Dr Gordon has received personal fees from AbbVie, Almirall, Amgen, BMS, Dermavant, Dermira, Lilly, Janssen, Kyowa Hakko Kirin, LEO Pharma, Novartis, Pfizer, Sun Pharma, and UCB and grants from BMS, Lilly, and UCB. Dr Irvine has received person fees from AbbVie, LEO Pharma, Lilly, Novartis, and Sanofi/Regeneron, and has received a grant from the UK National Institute for Health Research (research arm of the UK Department of Health) as co-principal investigator of a clinical trial comparing MTX with cyclosporine in children with severe atopic dermatitis. Dr Kirkorian has received honoraria from Verrica. Dr Lara-Corrales has served as an advisory board member for Ipsen, LEO Pharma, Lilly, Novartis, Pfizer, and Sanofi Genzyme; as a consultant for AbbVie, Avicanna, Janssen, Johnson & Johnson, Loreal, Pfizer, Pierre Fabre, Sanofi Genzyme, and Valeant; as a speaker for AbbVie, Amgen, Novartis, and Sanofi Genzyme; and has served as a site investigator for AbbVie, Clementia Pharmaceuticals, Janssen, Lilly, and, Mayne Pharma. Dr Jill Lindstrom has received consulting fees from AbbVie, AnaptysBio, Arena Pharmaceuticals, Aristea, Incyte, and Priovant. Dr Amy S. Paller has served as an investigator for AbbVie, Applied Pharma Research, Dermavant, Eli Lilly, Incyte, Janssen, Krystal, Regeneron, and UCB; Consultant for Aegerion Pharma, Azitra, BioCryst, Boehringer-Ingelheim, Bristol Myers Squibb, Castle Creek, Eli Lilly, Janssen, Krystal, LEO Pharma, Novartis, Regeneron, Sanofi/Genzyme, Seanergy, TWI Biotechnology, and UCB, and on the data safety monitoring board for AbbVie, Abeona, Catawba, Galderma, and InMed. Author Begolka has served as an advisory board member for Incyte and Pfizer, and has received a grant from Pfizer. Dr Tom has served as a site investigator for clinical trials for Janssen, Regeneron, Incyte, Pfizer, Dermira, Eli Lilly, and AbbVie, and has been on data safety committees for LEO Pharma. Dr Voorhees has received research grants from AbbVie, Celgene, and Lilly; has served as an advisory board member for BMS, Boehringer Ingelheim, Celgene, Novartis, and UCB; and had received consulting fees from Amgen. Dr Vleugels has received consulting fees from AbbVie, Pfizer, and Priovant. Dr Lee has received consulting fees from AbbVie and Krystal Biotech; served as an investigator for AbbVie, Amryt, Arcutis, BMS, Castle Creek Biosciences, Celgene, Galderma, Incyte, Janssen, Kiniksa, Lilly, Mayne Pharma, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Target Pharma, Trevi Therapeutics, and UCB; and has served as an advisory board member for Lilly, Novartis, Pfizer, and Regeneron. Dr Davies has received a fellow stipend from Pediatric Dermatology Research Alliance (PeDRA). Dr Siegfried has received consulting fees from AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica; has received honoraria from Regeneron, Sanofi Genzyme, and Verrica; has served on data safety monitoring boards for LEO Pharma, Novan, Pfizer, and UCB; participated in contracted research for AI Therapeutics; served as principal investigator for Janssen, and her institution has received fees related to clinical trials from Janssen, Lilly, Pierre Fabre, Regeneron, and Verrica and in support of a 2020-2021 pediatric dermatology fellowship from Pfizer. Dr Chiu, Dr Callen, Dr Castello-Soccio, Dr Co, Author Hanna, Dr Kim, and Dr Reyes have no conflicts of interest to declare.

Importance: The use of patient-reported outcome measures (PROMs) potentially holds promise as an opportunity to improve outcomes and quality of care for patients with skin disease, but the routine use of PROMs remains limited. While the Patient-Reported Outcomes Measurement Information System (PROMIS) has several strengths and domains relevant to those with chronic skin disease, it is not clear which are most useful., Objective: To determine which PROMIS domains are most meaningful to those with chronic skin disease to develop a PROMIS profile that effectively captures the experience of living with these skin diseases., Design, Setting, and Participants: This cross-sectional study was based on data gathered from an internet survey that was administered to a sample of adult respondents in the US on the Prolific Platform and ResearchMatch and through the National Psoriasis Foundation. A list of PROMIS domains relevant to chronic skin disease was developed through literature review. These domains were included in a best-worst scaling exercise, in which participants were shown 12 sets of 4 domains and asked to choose which domain in each set was the most important and least important to their experience. Participants completed the survey between December 2022 and June 2023. Data were analyzed in June 2023., Main Outcomes and Measures: Ratio-scaled preference score for each of the domains., Results: Of 939 total participants, 559 (59.5%) were female, 20 (2.1%) gender nonconforming, 7 (0.7%) transgender men, and 1 (0.1%) transgender women; there were 4 American Indian/Alaska Native (0.4%), 50 Asian (5.3%), 63 Black (6.7%), 66 Hispanic or Latino/a/x (7.0%), 2 Native Hawaiian/Pacific Islander (0.2%), 749 White (79.8%), and 42 multiracial individuals (4.5%). The survey was completed by 200 participants with acne, 316 with psoriasis, 199 with atopic dermatitis, and 224 with various chronic skin diseases. For those with acne, the highest-scored domains were body image (15.66), appearance (14.96), life satisfaction (11.29), depression (9.25), and anxiety (9.18). For those with psoriasis, the highest-scored domains were life satisfaction (11.31), appearance (11.05), itch (10.98), pain (9.97), and body image (8.75). For those with atopic dermatitis, the highest-scored domains were itch (12.60), life satisfaction (11.65), appearance (11.40), body image (11.25), and pain (10.03)., Conclusion and Relevance: The results of this study suggest that body image, appearance, life satisfaction, itch, pain, anxiety, and depression were highly rated across the surveys. By identifying the PROMIS domains most important to individuals with chronic skin disease, clinicians can choose the domains that are most relevant to patients. In addition, this may guide the construction of a PROMIS profile that effectively captures the experience of living with these skin diseases and can serve as a patient-reported measure of disease severity and treatment effectiveness.

Objective: Patients with atopic dermatitis (AD) have low treatment satisfaction. In this study, we evaluated the humanistic burden, treatment satisfaction, and treatment expectations in patients with AD in the United States., Methods: Adults with AD recruited through the National Eczema Association and clinical sites completed a web-based survey comprising the Patient-Oriented SCORing Atopic Dermatitis (PO-SCORAD), Dermatology Life Quality Index; Work Productivity and Activity Impairment Questionnaire-Atopic Dermatitis; Treatment Satisfaction Questionnaire for Medication (TSQM); and answered questions on healthcare provider (HCP) visits, treatment history, and treatment goals. Descriptive analyses were performed to compare participants by severity., Results: Among 186 participants (mean [standard deviation] age 39.7 [15.3] years, 79.6% female), 26.9%, 44.6%, and 26.3% of the participants had mild, moderate, or severe AD, respectively, based on PO-SCORAD. Greater disease severity was associated with a greater impact on work and daily life, decreased TSQM scores, and increased HCP visits. Corticosteroid topical cream or ointment (53.8%) and oral antihistamines (31.2%) were most commonly used for the treatment of AD. Participants reported declining/stopping/changing AD treatment due to the potential for side effects or lack of efficacy. 'Leading normal lives' (28.0%) and 'being itch-free' (33.9%) were important treatment goals., Conclusions: Individuals with AD, especially severe disease, face a considerable humanistic burden even while using treatment.

Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication., (© 2023 The Authors. Pediatric Dermatology published by Wiley Periodicals LLC.)

Background: Emerging digital measures and clinical outcome assessments (COAs) leveraging digital health technologies (DHTs) could address the need for objective, quantitative measures of symptoms of atopic dermatitis (AD), such as nocturnal scratching. Development of such measures needs to be supported by evidence reflecting meaningfulness to patients., Objectives: To assess nocturnal scratching as a concept of interest associated with meaningful aspects of health of patients with AD (adults and children); and to explore patient-centred considerations for novel COAs measuring nocturnal scratch using DHTs., Methods: Phase 1 evaluated disease impacts on everyday life and the lived experience with nocturnal scratching through qualitative interviews of AD patients and caregivers. Phase 2 deployed a quantitative survey to a sample of AD patients as well as caregivers., Results: Four cohorts with various AD severity levels participated in Phase 1: (1) adults with AD ( n  = 15), (2) their caregivers/spouses/partners ( n  = 6), (3) children with AD ( n  = 14), and (4) their adult caregivers ( n  = 14). Findings were used to develop a conceptual model for nocturnal scratching as a potential concept of interest. The Phase 2 survey was completed by 1349 of 27640 invited adults with AD and caregivers of children with AD. The most burdensome aspects of AD reported were itchy skin and scratching. Overall, ∼65% of participants reported nocturnal scratching ≥1 day/week, resulting in ∼1-1.4 h of sleep lost per night. In all, 85%-91% of respondents considered it at least somewhat valuable that a treatment reduces night-time scratching. About 50% reported willingness to use technology to this end and ∼25% were unsure., Conclusion: Our results represented by the conceptual model confirm that nocturnal scratch is a concept of interest related to meaningful aspects of health for patients with AD and therefore is worth being captured as a distinct outcome for clinical and research purposes. DHTs are suitable tools presenting an important measurement opportunity to assess and evaluate occurrence, frequency, and other parameters of nocturnal scratching as a disease biomarker or COA of treatment efficacy., Competing Interests: Lucia Cesnakova and Jennifer C. Goldsack are employees of the Digital Medicine Society, the sponsor of this study. The other authors are employees of their respective organizations. Carrie A. Northcott, Doina Sirbu and Jérémy Lambert are shareholders of their respective organizations., (© 2023 Digital Medicine Society (DiME). Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Competing Interests: None disclosed.

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., Competing Interests: MEJ has no conflicts to disclose; IJT is a salaried employee of the National Eczema Association, WB has no conflicts to disclose, EL has no conflicts to disclose, AK has no conflicts to disclose, ARL is a salaried employee of the National Eczema Association, ELS reports personal fees from AbbVie, Amgen, Arena Pharmaceuticals, Aslan Pharma, Boston Consulting Group, Collective Acumen, LLC (CA), Dermira, Eli Lilly, Evidera, ExcerptaMedica, Forte Bio RX, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa Kirin Pharmaceutical Development, Leo Pharm, Medscape LLC, Merck, Pfizer, Physicians World LLC, Regeneron, Roivant, Sanofi‐Genzyme, Trevi therapeutics, Valeant, WebMD. These potential conflicts of interest have been reviewed and managed by OHSU, WSB is a salaried employee of the National Eczema Association, has received grants from Pfizer, and advisory board honoraria from Pfizer and Amgen., (© 2023 The National Eczema Association and Oregon Health & Science University. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Atopic dermatitis (AD) and food allergies are more prevalent and more severe in people with skin of color than White individuals. The American College of Allergy, Asthma, and Immunology (ACAAI) sought to understand the effects of racial disparities among patients with skin of color with AD and food allergies. The ACAAI surveyed its members (N = 200 completed), conducted interviews with health care providers and advocacy leaders, and hosted a roundtable to explore the challenges of diagnosis and management of AD and food allergies in people with skin of color and to discuss potential solutions. Most of the survey respondents (68%) agreed that racial disparities make it difficult for people with skin of color to receive adequate treatment for AD and food allergies. The interviews and roundtable identified access to care, burden of costs, policies and infrastructure that limit access to safe foods and patient education, and inadequate research involving people with skin of color as obstacles to care. Proposed solutions included identifying ways to recruit more people with skin of color into clinical trials and medical school, educating health care providers about diagnosis and treating AD and food allergy in people with skin of color, improving access to safe foods, creating and disseminating culturally appropriate materials for patients, and working toward longer appointment times for patients who need them. Challenges in AD and food allergy in persons with skin of color were identified by the ACAAI members. Solutions to these challenges were proposed to inspire actions to mitigate racial disparities in AD and food allergy., (Copyright © 2023. Published by Elsevier Inc.)

Importance: Patient values and preferences can inform atopic dermatitis (AD) care. Systematic summaries of evidence addressing patient values and preferences have not previously been available., Objective: To inform American Academy of Allergy, Asthma & Immunology (AAAAI)/American College of Allergy, Asthma and Immunology (ACAAI) Joint Task Force on Practice Parameters AD guideline development, patient and caregiver values and preferences in the management of AD were systematically synthesized., Evidence Review: Paired reviewers independently screened MEDLINE, Embase, PsycINFO, and CINAHL databases from inception until March 20, 2022, for studies of patients with AD or their caregivers, eliciting values and preferences about treatment, rated risk of bias, and extracted data. Thematic and inductive content analysis to qualitatively synthesize the findings was used. Patients, caregivers, and clinical experts provided triangulation. The GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative Research) informed rating of the quality of evidence., Findings: A total of 7780 studies were identified, of which 62 proved eligible (n = 19 442; median age across studies [range], 15 years [3-44]; 59% female participants). High certainty evidence showed that patients and caregivers preferred to start with nonmedical treatments and to step up therapy with increasing AD severity. Moderate certainty evidence showed that adverse effects from treatment were a substantial concern. Low certainty evidence showed that patients and caregivers preferred odorless treatments that are not visible and have a minimal effect on daily life. Patients valued treatments capable of relieving itching and burning skin and preferred to apply topical corticosteroids sparingly. Patients valued a strong patient-clinician relationship. Some studies presented varied perspectives and 18 were at high risk for industry sponsorship bias., Conclusions and Relevance: In the first systematic review to address patient values and preferences in management of AD to our knowledge, 6 key themes that may inform optimal clinical care, practice guidelines, and future research have been identified.

Background: Previous studies have documented the high patient and caregiver burden associated with atopic dermatitis (AD). Less is known about the factors-especially those related to treatment options and the delivery of medical care-that may relate to burden and unmet needs among patients and their caregivers., Objective: Our primary aim was to characterize and compare health-related quality of life, long-term control of symptoms, satisfaction with treatments, the financial burden, and the prevalence of patient-centered care among adult and pediatric patients with AD in 8 developed nations., Methods: We developed a 53-item anonymous online survey for adult patients and caregivers of children with AD (N = 3171; self-reported disease severity: 8.2% clear, 33.2% mild, 41.1% moderate, 17.6% severe). The survey included questions across 7 domains selected by a steering committee of 11 patient organizations that advocate for patients with AD in the 8 countries. We used validated instruments when available including the 5-level EuroQol five-dimensional questionnaire and the Atopic Dermatitis Control Tool. The survey was offered in 5 languages and promoted through social media and other communication channels of the patient organizations., Results: The health-related quality-of-life scores for adult patients with AD (driven by 2 domains: pain/discomfort and anxiety/depression) were worse than those reported for asthma and type 2 diabetes in previous studies (0.72; 95% CI, 0.65-0.78). Patients and caregivers reported substantial financial impacts even in countries with government-funded health care systems, though the greatest impact was in the United States. In all countries, adults reported better control of symptoms than children, but neither group nor any nationality reported adequate control on average (rescaled mean, 57.5; 95% CI, 56.1-58.9), and control correlated negatively with disease severity. Similarly, satisfaction with treatments, which was moderate across countries on average, was much lower for respondents with more severe disease symptoms (F(3,3165) = 5.5; P < .001). Patients who saw a specialist (a dermatologist or an allergist) instead of a general practitioner for AD care indicated better long-term control of symptoms (by 4 points on average on the 100-point scale; 95% CI, 2.6-5.4; P < .001). Finally, self-management training and shared decision making were uncommonly reported by patients in all countries except by respondents from the United States, but both were associated with better long-term control of symptoms and higher satisfaction., Conclusions: The burden of AD, evaluated as health-related quality-of-life detriments, financial impacts, and uncontrolled symptoms, is significant and highest for patients with more severe atopic dermatitis who report greater challenges in achieving symptom resolution with existing treatments and approaches to care. The better outcomes associated with respondents who saw specialists suggest that patients, especially those with more severe AD, might benefit from medical care that is guided by providers with more in-depth knowledge of this complex condition. Finally, wider use of patient-centered care practices (specifically, self-management training and shared decision making) could improve outcomes and boost satisfaction with treatments for AD, though more research on this topic is warranted., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Atopic dermatitis (AD) is associated with elevated financial costs, including out-of-pocket (OOP) expenses. Yet, the full burden of OOP expenses in children with AD is poorly understood., Objectives: We sought to characterise categories, impact, and associations of caregiver-reported OOP AD healthcare expenses for US children., Methods: An online survey was administered to National Eczema Association members ( N  = 113 502). Inclusion criteria (US resident; respondent age ≥18; self or caregiver report of AD diagnosis) was met by 77.3% (1118/1447) of those who completed the questionnaire., Results: Caregivers of children (<18 years) with AD reported increased healthcare provider (HCP) visits, comorbid food allergy, cutaneous infections, and topical antimicrobial use ( p  < 0.005 for all), and increased OOP expenses for hospitalisation, emergency room visits, emollients, hygiene/bathing products, childcare, and specialised cleaning products, and clothing/bedding ( p  < 0.05 for all) compared to adults with AD. Children with AD had increased median total yearly OOP expenditures ($860 vs. $500, p  = 0.002) and were more likely to spend ≥$1000 OOP per year (48.9% vs. 40.0%, p  = 0.03). In children, yearly OOP expenses ≥$1000 were associated with increased AD severity, flares, HCP visits, prescription polypharmacy, and step-up therapy use ( p  < 0.005 for all) compared with adults. Predictors of harmful financial impact among children included black race (adjusted OR [95% confidence interval]: 3.86 [1.66-8.98] p  = 0.002) and ≥$1000 annual OOP expenditures (6.98 [3.46-14.08], p  < 0.0001)., Conclusion: Children with AD have unique and increased OOP expenses that are associated with significant disease burden. Strategies are needed to reduce OOP costs and improve clinical outcomes in children with AD., Competing Interests: Raj Chovatiya has served as an advisory board member, consultant, and/or investigator for AbbVie, Arcutis, Arena, Beiersdorf, Bristol Myers Squibb, Dermavant, Eli Lilly and Company, EPI Health, Incyte, L'Oréal, National Eczema Association, Pfizer Inc., Regeneron, Sanofi, and UCB, and speaker for AbbVie, Dermavant, Eli Lilly and Company, Incyte, Pfizer Inc., Regeneron, Sanofi, and UCB. Wendy Smith Begolka has served as an advisory board member and/or investigator for Incyte and Pfizer. Jonathan Silverberg reports personal fees from Abbvie, Afyx, Arena, Asana, BioMX, Bluefin, Bodewell, Boehringer‐Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Kiniksa, Leo, Luna, Menlo, Novartis, Pfizer, RAPT, Regeneron, Sanofi‐Genzyme; institution received grants from Galderma. Isabelle Thibau declares no competing interests., (© 2022 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Atopic dermatitis (AD) is associated with substantial financial cost, including increased out-of-pocket (OOP) expenses. Associations and impact of OOP costs are poorly understood., Objective: The aim of the study was to characterize the impact and associations of OOP health care expenses for AD., Methods: A 25-question online survey was administered to National Eczema Association members (N = 113,502). Inclusion criteria (US residents aged ≥18 years; self-reported AD or primary caregiver of individual with AD) were met by 77.3% (1118 of 1447)., Results: Respondents with monthly OOP expenses greater than $200 were more likely to have increased AD severity, flares, health care provider visits, prescription polypharmacy, use of step-up therapy, frequent skin infections, and poorer disease control ( P < 0.005 for all). Respondents with OOP yearly expenditures greater than $1000 had similar associations and additionally increased rates of comorbid asthma, allergic rhinitis, and anxiety/depression ( P < 0.005 for all). A total of 64.6% (n = 624) reported harmful household financial impact of OOP expenses. Predictors of harmful impact included severe AD (adjusted odds ratio [95% confidence interval], 2.62 [1.11-6.19], P = 0.04), comorbid asthma (1.42 [1.07-1.87], P = 0.03), 5 health care provider visits or more in a year (2.80 [1.62-4.82], P = 0.0007), greater than $200 OOP monthly expenditures (2.16 [1.45-3.22], 0.0006), and $1000 annual OOP expenditures or more (4.56 [3.31-6.27], P < 0.0001)., Conclusions: Out-of-pocket expenses for AD significantly impact household finances. Clinical interventions are needed to minimize OOP expenses while optimizing care outcomes.Capsule Summary:• Atopic dermatitis (AD) is associated with significant financial cost, including increased out-of-pocket (OOP) expenses, although the impact and associations of OOP health care expenses for AD management are not well understood.• The OOP health care expenses related to AD are associated with increased disease severity and health care utilization and significantly impact the household finances of patients and caregivers.• Health care providers should be mindful of the OOP financial burden related to AD management and engage in shared decision making to create a treatment plan that is practical and effective and minimizes household financial impact., Competing Interests: R.C. reports personal fees from AbbVie and Regeneron­Sanofi. J.I.S. reports personal fees from AbbVie, Anaptysbio, Asana, EliLilly, Galderma, GlaxoSmithKline, Kiniksa, Leo, Menlo, Pfizer, Realm, Regeneron­Sanofi, and Roivant and grants from GlaxoSmithKline, Regeneron­Sanofi, and Galderma. The other authors have no funding or conflicts of interest to declare., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Contact Dermatitis Society.)

Black race is associated with increased atopic dermatitis (AD) severity and healthcare resource utilization. However, the burden of out-of-pocket (OOP) expenses among black individuals with AD is not well understood. We sought to characterize the categories and impact of OOP healthcare expenses associated with AD management among black individuals. A 25-question voluntary online survey was administered to National Eczema Association members (N = 113,502). Inclusion criteria (US residents age ≥ 18 years; self-report of AD or primary caregivers of individuals with AD) was met by 77.3% (1118/1447) of respondents. Black individuals with AD were younger, had lower household income, Medicaid, urban residence, poor AD control and frequent skin infections (P ≤ 0.02). Blacks vs. non-blacks reported more OOP costs for prescription medications covered (74.2% vs. 63.6%, P = 0.04) and not covered (65.1% vs. 46.5%, P = 0.0004) by insurance, emergency room visits (22.1% vs. 11.8%, P = 0.005), and outpatient laboratory testing (33.3% vs. 21.8%, P = 0.01). Black race was associated with increased household financial impact from OOP expenses (P = 0.0009), and predictors of financial impact included minimally controlled AD (adjusted OR [95% CI] 13.88 [1.63-117.96], P = 0.02), systemic therapy (4.34 [1.63-11.54], 0.003), > $200 monthly OOP expenses (14.28 [3.42-59.60], P = 0.0003), and Medicaid (4.02 [1.15-14.07], P = 0.03). Blacks with Medicaid had higher odds of harmful financial impact (3.32 [1.77-6.24], P = 0.0002) than those of black race (1.81 [1.04-3.15], P = 0.04) or with Medicaid (1.39 [1.02-1.88], P = 0.04) alone. Black race is associated with increased OOP costs for AD and significant household financial impact. Targeted interventions are needed to address financial disparities in AD., (© 2021. The Author(s).)

Background: Atopic dermatitis is a pruritic chronic condition associated with significant sleep disturbance, inattention, and sometimes behavioral problems. Enhancing resiliency in children with atopic dermatitis may promote coping strategies to improve quality of life. Positive psychology is one strategy that can be used to strengthen resiliency., Objective: Our objective was to identify positive psychology concepts mentioned by children with atopic dermatitis and their parent to inform strategies to strengthen resiliency in children with atopic dermatitis., Methods: A total of 20 patient-parent dyads were interviewed to share their experience with atopic dermatitis to help develop a novel psychologic intervention for atopic dermatitis. Patients were 8 to 17 years old and diagnosed with atopic dermatitis. Trained coders analyzed transcripts using a coding dictionary developed based on Seligman's PERMA (positive emotion, engagement, relationships, meaning, and accomplishment) model of positive psychology. The frequency of unprompted mentions of PERMA themes and relevant quotations was captured. Transcripts were also separately coded for resiliency, which is the ultimate goal of PERMA., Results: Positive psychology concepts were mentioned by 100% (20/20) of children and 95% (19/20) of parents. Engagement and relationships, both negative and positive aspects, were the most common unprompted PERMA themes mentioned by children (14/20, 70%) and parents (13/20, 65%). Emotion elicited the most negative comments from children (19/20, 95%) and parents (17/20, 85%). When analyzed for resiliency, 8 participants were identified with at least one resiliency code. On average, participants with a resiliency code mentioned PERMA concepts 9.1 (SD 4.7) times compared to those who mentioned none (mean 5.9, SD 4.6) (P=.14). When participants were stratified by disease severity, on average, more positive psychology concepts were mentioned by patients with mild atopic dermatitis (mean 13, SD 3.0) than those with moderate symptoms (mean 6.2, SD 4.9) or severe symptoms (mean 6.1, SD 4.0) (P=.03)., Conclusions: Among PERMA themes, engagement and relationships are the two most commonly mentioned categories for children with atopic dermatitis. Strategies targeting PERMA such as affirmations and positive reframing may improve psychosocial well-being and resiliency in pediatric atopic dermatitis. Future directions will look at incorporating "positive medicine" into atopic dermatitis treatment to not only relieve symptoms but also strengthen positive aspects of life., (©Terry M Lou, Kenneth L Zhang, Noël C Slesinger, Michelle Taddeo, Eloisa Serrano, Wendy Smith Begolka, Korey Capozza, Amy S Paller, James W Griffith, Anna B Fishbein. Originally published in JMIR Pediatrics and Parenting (https://pediatrics.jmir.org), 14.09.2022.)

Background: Bleach bathing is frequently recommended to treat atopic dermatitis (AD), but its efficacy and safety are uncertain., Objective: To systematically synthesize randomized controlled trials (RCTs) addressing bleach baths for AD., Methods: We searched MEDLINE, EMBASE, CENTRAL, and GREAT from inception to December 29, 2021, for RCTs assigning patients with AD to bleach vs no bleach baths. Paired reviewers independently and in duplicate screened records, extracted data, and assessed risk of bias (Cochrane version 2) and GRADE quality of evidence. We obtained unpublished data, harmonized individual patient data and did Frequentist and Bayesian random-effects meta-analyses., Results: There were 10 RCTs that enrolled 307 participants (median of mean age 7.2 years, Eczema Area Severity Index baseline mean of means 27.57 [median SD, 10.74]) for a median of 6 weeks (range, 4-10). We confirmed that other trials registered globally were terminated. Bleach baths probably improve AD severity (22% vs 32% improved Eczema Area Severity Index by 50% [ratio of means 0.78, 95% credible interval 0.59-0.99]; moderate certainty) and may slightly reduce skin Staphylococcal aureus colonization (risk ratio, 0.89 [95% confidence interval, 0.73-1.09]; low certainty). Adverse events, mostly dry skin and irritation, along with itch, patient-reported disease severity, sleep quality, quality of life, and risk of AD flares were not clearly different between groups and of low to very low certainty., Conclusion: In patients with moderate-to-severe AD, bleach baths probably improve clinician-reported severity by a relative 22%. One in 10 will likely improve severity by 50%. Changes in other patient-important outcomes are uncertain. These findings support optimal eczema care and the need for additional large clinical trials., Trial Registration: PROSPERO Identifier: CRD42021238486., (Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

DISCLOSURES: No funding contributed to the writing of this commentary. Smith Begolka, Butler, and Guadalupe are salaried employees of the National Eczema Association, which has received grants and sponsorship awards from a variety of industry partners, including AbbVie, Eli Lilly, Incyte, LEO Pharma, Pfizer, Regeneron, and Sanofi. Smith Begolka has received grant funding from Pfizer and advisory board honoraria from Pfizer and Incyte. Butler and Guadalupe have received advisory board honoraria from Incyte.

Background: Atopic dermatitis (AD) causes sleep disturbance but the epidemiology is not known., Objective: To estimate the US prevalence of sleep disturbance and its impact on psychological and neurocognitive function., Methods: We conducted a cross-sectional survey of 180 parent-child dyads with AD using stratified sampling based on disease severity (Patient Oriented Eczema Measure: mild [n = 30), moderate (n = 75) or severe (n = 75]), age, and race (White or Black or African American or other). Symptoms of sleep and psychologic health were assessed using the Patient-Reported Outcome Measurement Information System. To estimate the prevalence of sleep disturbance, we calculated weights using poststratification adjustment making marginal frequencies of AD severity, race, and age similar to marginal frequencies in the 2007 National Survey of Children's Health. Unweighted regression models examined associations with sleep disturbance., Results: In children age 5 to 17 years with AD, we estimated that sleep disturbance occurred in 66.9% (95% confidence interval, 53.3% to 80.5%; 3,116,305 children). The odds of severe sleep disturbance (worse than 95% of US children) were highest in moderate to severe versus mild AD (2.03 [1.00-4.10]; P = .0495; compared with 8.68 [1.82-41.49]; P = .0068). Predictors of parent proxy-reported sleep disturbance were itch intensity (adjusted β [95% confidence interval] 1.33 [0.62-2.04]) and low income (<$50,000: 6.64 [2.05-11.23]; and $50,000 to less than 100,000: 4.75 [0.35-9.14]). Controlling for disease severity, itch intensity, and significant sociodemographics-parent-proxy, reported sleep disturbance was associated with increased severity of sleep-related impairment, depression, fatigue, and anxiety, in addition to worse inattention and impulsivity. In fully adjusted models, children who self-reported sleep disturbance (T-score ≥60) had increased odds of sleep-related impairment (1.20 [1.11-1.29]), depression (1.13 [1.03, 1.24]), fatigue (1.28 [1.06-1.54]), and anxiety (1.16 [1.02-1.31])., Conclusions: Sleep disturbance is a common symptom of AD. It affects about 3 million US children and is associated with neuropsychiatric impairment, including depression, anxiety, and inattention. Clinicians should screen for these symptoms in school-aged children, particularly those with moderate to severe AD., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Direct insurance claims tabulation and risk adjustment statistical methods can be used to estimate health care costs associated with various diseases. In this third manuscript derived from the new national Burden of Skin Disease Report from the American Academy of Dermatology, a risk adjustment method that was based on modeling the average annual costs of individuals with or without specific diseases, and specifically tailored for 24 skin disease categories, was used to estimate the economic burden of skin disease. The results were compared with the claims tabulation method used in the first 2 parts of this project. The risk adjustment method estimated the direct health care costs of skin diseases to be $46 billion in 2013, approximately $15 billion less than estimates using claims tabulation. For individual skin diseases, the risk adjustment cost estimates ranged from 11% to 297% of those obtained using claims tabulation for the 10 most costly skin disease categories. Although either method may be used for purposes of estimating the costs of skin disease, the choice of method will affect the end result. These findings serve as an important reference for future discussions about the method chosen in health care payment models to estimate both the cost of skin disease and the potential cost impact of care changes., (Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

There are an increasing number and variety of dermatologic surgical procedures performed safely in the office setting. This evidence-based guideline addresses important clinical questions that arise regarding the use and safety of local anesthesia for dermatologic office-based procedures. In addition to recommendations for dermatologists, this guideline also takes into account patient preferences while optimizing their safety and quality of care. The clinical recommendations presented here are based on the best evidence available as well as expert opinion., (Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Over the course of their nearly 30-year history, the ABCD(E) criteria have been used globally in medical education and in the lay press to provide simple parameters for assessment of pigmented lesions that need to be further evaluated by a dermatologist. In this article, the efficacy and limitations of the ABCDE criteria as both a clinical tool and a public message will be reviewed., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Atopic dermatitis 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 atopic dermatitis management and care, providing recommendations based on the available evidence. In this third of 4 sections, treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed, including indications for use and the risk-benefit profile of each treatment option., (Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

The appropriate use criteria process synthesizes evidence-based medicine, clinical practice experience, and expert judgment. The American Academy of Dermatology in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery has developed appropriate use criteria for 270 scenarios for which Mohs micrographic surgery (MMS) is frequently considered based on tumor and patient characteristics. This document reflects the rating of appropriateness of MMS for each of these clinical scenarios by a ratings panel in a process based on the appropriateness method developed by the RAND Corp (Santa Monica, CA)/University of California-Los Angeles (RAND/UCLA). At the conclusion of the rating process, consensus was reached for all 270 (100%) scenarios by the Ratings Panel, with 200 (74.07%) deemed as appropriate, 24 (8.89%) as uncertain, and 46 (17.04%) as inappropriate. For the 69 basal cell carcinoma scenarios, 53 were deemed appropriate, 6 uncertain, and 10 inappropriate. For the 143 squamous cell carcinoma scenarios, 102 were deemed appropriate, 7 uncertain, and 34 inappropriate. For the 12 lentigo maligna and melanoma in situ scenarios, 10 were deemed appropriate, 2 uncertain, and 0 inappropriate. For the 46 rare cutaneous malignancies scenarios, 35 were deemed appropriate, 9 uncertain, and 2 inappropriate. These appropriate use criteria have the potential to impact health care delivery, reimbursement policy, and physician decision making on patient selection for MMS, and aim to optimize the use of MMS for scenarios in which the expected clinical benefit is anticipated to be the greatest. In addition, recognition of those scenarios rated as uncertain facilitates an understanding of areas that would benefit from further research. Each clinical scenario identified in this document is crafted for the average patient and not the exception. Thus, the ultimate decision regarding the appropriateness of MMS should be determined by the expertise and clinical experience of the physician., (© 2012 by the American Society for Dermatologic Surgery, Inc., and the American Academy of Dermatology, Inc. Published by Wiley Periodicals, Inc.)

The American Academy of Dermatology and the American Society of Plastic Surgeons, with the support of other sister societies, conducted the Facial Soft-Tissue Fillers: Assessing the State of the Science conference in December of 2009. The American Academy of Dermatology and the American Society of Plastic Surgeons established a panel of leading experts in the field of soft-tissue fillers-from researchers to clinicians-and other stakeholders for the conference to examine and discuss issues of patient safety, efficacy, and effectiveness in relation to the approved and off-label use of soft-tissue fillers, and other factors, including the training and level of experience of individuals administering fillers. This report represents the systematic literature review that examines comprehensively the available evidence and gaps in the evidence related to soft-tissue fillers, to inform and support the work of the state-of-the-science conference panel. This evidence-based medicine review will serve as the foundation for future evidence-based medicine reports in this growing field., (Copyright © 2011 American Academy of Dermatology, Inc. and American Society of Plastic Surgeons. Published by Mosby, Inc. All rights reserved.)

The American Academy of Dermatology and the American Society of Plastic Surgeons, with the support of other sister societies, conducted the Facial Soft-Tissue Fillers: Assessing the State of the Science conference in December of 2009. The American Academy of Dermatology and the American Society of Plastic Surgeons established a panel of leading experts in the field of soft-tissue fillers-from researchers to clinicians-and other stakeholders for the conference to examine and discuss issues of patient safety, efficacy, and effectiveness in relation to the approved and off-label use of soft-tissue fillers, and other factors, including the training and level of experience of individuals administering fillers. This report summarizes the deliberations and key points made by the panel and presenters to the panel, and includes a summary of the panel's near-term and longer term recommendations for next steps to help guide future efforts to address the safety, efficacy, and effectiveness of facial soft-tissue fillers. This report represents the panel's assessment of the medical knowledge available on facial soft-tissue fillers at the time of the conference., (Copyright © 2011 American Academy of Dermatology, Inc. and American Society of Plastic Surgeons. Published by Mosby, Inc. All rights reserved.)

Summary: : The American Society of Plastic Surgeons and the American Academy of Dermatology, with the support of other sister societies, conducted the Facial Soft-Tissue Fillers: Assessing the State of the Science conference in December of 2009. The American Society of Plastic Surgeons and the American Academy of Dermatology established a panel of leading experts in the field of soft-tissue fillers-from researchers to clinicians-and other stakeholders for the conference to examine and discuss issues of patient safety, efficacy, and effectiveness in relation to the approved and off-label use of soft-tissue fillers, and other factors, including the training and level of experience of individuals administering fillers. This report represents the systematic literature review that examines comprehensively the available evidence and gaps in the evidence related to soft-tissue fillers, to inform and support the work of the state-of-the-science conference panel. This evidence-based medicine review will serve as the foundation for future evidence-based medicine reports in this growing field.

Background: The periventricular subventricular zone (SVZ) contains stem cells and is an area of active neurogenesis and migration. Since inflammation can reduce neurogenesis, we tested whether Theiler's murine encephalomyelitis virus (TMEV) induces inflammation and reduces neurogenesis in the SVZ., Methods: We performed immmunohistochemistry for the hematopoietic cell marker CD45 throughout the central nervous system and then examined neuroblasts in the SVZ., Results: CD45+ activation (inflammation) occurred early in the forebrain and preceded cerebellar and spinal cord inflammation. Inflammation in the brain was regionally stochastic except for the SVZ and surrounding periventricular regions where it was remarkably pronounced and consistent. In preclinical mice, SVZ neuroblasts emigrated into inflamed periventricular regions. The number of proliferating phoshpohistone3+ cells and Doublecortin+ (Dcx) SVZ neuroblasts was overall unaffected during the periods of greatest inflammation. However the number of Dcx+ and polysialylated neural cell adhesion molecule (PSA-NCAM+) SVZ neuroblasts decreased only after periventricular inflammation abated., Conclusion: Our results suggest that after TMEV infection, the SVZ may mount an attempt at neuronal repair via emigration, a process dampened by decreases in neuroblast numbers.

CD4+CD25+ T regulatory (T(R)) cells are an important regulatory component of the adaptive immune system that limit autoreactive T cell responses in various models of autoimmunity. This knowledge was generated by previous studies from our lab and others using T(R) cell supplementation and depletion. Contrary to dogma, we report here that injection of anti-CD25 mAb results in the functional inactivation, not depletion, of T(R) cells, resulting in exacerbated autoimmune disease. Supporting this, mice receiving anti-CD25 mAb treatment display significantly lower numbers of CD4+CD25+ T cells but no change in the number of CD4+FoxP3+ T(R) cells. In addition, anti-CD25 mAb treatment fails to both reduce the number of Thy1.1+ congenic CD4+CD25+ T(R) cells or alter levels of CD25 mRNA expression in treatment recipients. Taken together, these findings have far-reaching implications for the interpretation of all previous studies forming conclusions about CD4+CD25+ T(R) cell depletion in vivo.

The central nervous system (CNS) is an immunologically specialized organ. The blood-brain barrier regulates the passage of molecules and cells into the CNS. Robust immune responses occur in the CNS even though there is normally an absence of MHC molecules, lack of normal lymphatic drainage, and reduced immune surveillance. This review discusses the immunological elements of the healthy CNS and the pattern of responses that evolve during innate and adaptive immunity in this organ. We also discuss the contribution of astrocytes, cerebrovascular endothelial cells, microglia, macrophages, and dendritic cells to the integrity and pathology of the CNS during CD4+ T-cell autoimmune responses directed against neuroantigens.

The immunologic privilege of the central nervous system (CNS) makes it crucial that CNS resident cells be capable of responding rapidly to infection. Astrocytes have been reported to express Toll-like receptors (TLRs), hallmark pattern recognition receptors of the innate immune system, and respond to their ligation with cytokine production. Astrocytes have also been reported to respond to cytokines of the adaptive immune system with the induction of antigen presentation functions. Here we have compared the ability of TLR stimuli and the adaptive immune cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) to induce a variety of immunologic functions of astrocytes. We show that innate signals LPS- and poly I:C lead to stronger upregulation of TLRs and production of the cytokines IL-6 and TNF-alpha as well as innate immune effector molecules IFN-alpha4, IFN-beta, and iNOS compared with cytokine-stimulated astrocytes. Both innate stimulation and adaptive stimulation induce similar expression of the chemokines CCL2, CCL3, and CCL5, as well as similar enhancement of adhesion molecule ICAM-1 and VCAM-1 expression by astrocytes. Stimulation with adaptive immune cytokines, however, was unique in its ability to induce upregulation of MHC II and the functional ability of astrocytes to activate CD4(+) T cells. These results indicate potentially important and changing roles for astrocytes during the progression of CNS infection., (Copyright 2004 Wiley-Liss, Inc.)

Theiler's murine encephalomyelitis virus (TMEV) infection of the central nervous system (CNS) induces a chronic, progressive demyelinating disease in susceptible mouse strains characterized by inflammatory mononuclear infiltrates and spastic hind limb paralysis. Our lab has previously demonstrated a critical role for TMEV- and myelin-specific CD4(+) T cells in initiating and perpetuating this pathology. It has however, also been shown that the MHC class I loci are associated with susceptibility/resistance to TMEV infection and persistence. For this reason, we investigated the contribution of CD8(+) T cells to the TMEV-induced demyelinating pathology in the highly susceptible SJL/J mouse strain. Here we show that beta2M-deficient SJL mice have similar disease incidence rates to wild-type controls, however beta2M-deficient mice demonstrated earlier onset of clinical disease, elevated in vitro responses to TMEV and myelin proteolipid (PLP) epitopes, and significantly higher levels of CNS demyelination and macrophage infiltration at 50 days post-infection. beta2M-deficient mice also displayed a significant elevation in persisting viral titers, as well as an increase in macrophage-derived pro-inflammatory cytokine mRNA expression in the spinal cord at this same time point. Taken together, these results indicate that CD8(+) T cells are not required for clinical or histologic disease initiation or progression in TMEV-infected SJL mice. Rather, these data stress the critical role of CD4(+) T cells in this capacity and further emphasize the potential for CD8(+) T cells to contribute to protection from TMEV-induced demyelination.

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a chronic-progressive, immune-mediated CNS demyelinating disease and a relevant model of multiple sclerosis. Myelin destruction is initiated by TMEV-specific CD4(+) T cells targeting persistently infected CNS-resident APCs leading to activation of myelin epitope-specific CD4(+) T cells via epitope spreading. We examined the temporal development of virus- and myelin-specific T cell responses and acquisition of virus and myelin epitopes by CNS-resident APCs during the chronic disease course. CD4(+) T cell responses to virus epitopes arise within 1 wk after infection and persist over a >300-day period. In contrast, myelin-specific T cell responses are first apparent approximately 50-60 days postinfection, appear in an ordered progression associated with their relative encephalitogenic dominance, and also persist. Consistent with disease initiation by virus-specific CD4(+) T cells, CNS mononuclear cells from TMEV-infected SJL mice endogenously process and present virus epitopes throughout the disease course, while myelin epitopes are presented only after initiation of myelin damage (>50-60 days postinfection). Activated F4/80(+) APCs expressing high levels of MHC class II and B7 costimulatory molecules and ingested myelin debris chronically accumulate in the CNS. These results suggest a process of autoimmune induction in which virus-specific T cell-mediated bystander myelin destruction leads to the recruitment and activation of infiltrating and CNS-resident APCs that process and present endogenous myelin epitopes to autoreactive T cells in a hierarchical order.

Theiler's murine encephalomyelitis virus is an endemic murine pathogen that induces a demyelinating disease of the central nervous system in susceptible mouse strains. The disease is characterized by central nervous system mononuclear cell infiltration and presents as chronic, progressive paralysis. The expression of CC and C-x-C chemokines in the central nervous system of Theiler's murine encephalomyelitis virus-infected mice was examined throughout the disease course by ELISA and RT - PCR analysis. Central nervous system expression of MCP-1 and MIP-1alpha protein was evident by day 11 post Theiler's murine encephalomyelitis virus infection of SJL mice and continued throughout disease progression. MIP-1alpha, RANTES, MCP-1, C10, IP-10, and MIP-1beta mRNA was specifically expressed in the central nervous system and not the periphery following Theiler's murine encephalomyelitis virus infection. This was associated with development of clinical disease. These data suggest that the expression of multiple chemokines at particular times following viral infection is associated with demyelinating disease.

Multiple sclerosis is an immune-mediated demyelinating disease of unknown etiology that presents with either a chronic-progressive or relapsing-remitting clinical course. Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) and relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) in the SJL/J mouse are both relevant murine CD4+ T cell-mediated demyelinating models that recapitulate the multiple sclerosis disease phenotypes. To determine the cellular and molecular basis for these observed differences in clinical course, we quantitatively analyzed the temporal expression of pro- and antiinflammatory cytokine mRNA expression in the central nervous system (CNS) and the phenotype of the inflammatory mononuclear infiltrates. TMEV-infected SJL/J mice expressed IFN-gamma, TNF-alpha, IL-10, and IL-4 mRNA during the preclinical phase, and their levels continued to increase throughout the duration of the chronic-progressive disease course. These data correlated with the continued presence of both CD4+ T cells and F4/80+ macrophages within the CNS infiltrates. In contrast, SJL/J mice with PLP(139-151)-induced R-EAE displayed a biphasic pattern of CNS expression for the proinflammatory cytokines, IFN-gamma and TNF-alpha, with expression peaking at the height of the acute phase and relapse(s). This pattern correlated with dynamic changes in the CD4+ T cell and F4/80+ macrophage populations during relapsing-remitting disease progression. Interestingly, IL-4 message was undetectable until disease remission(s), demonstrating its potential role in the intrinsic regulation of ongoing disease, whereas IL-10 was continuously expressed, arguing against a regulatory role in either disease. These data suggest that the kinetics of cytokine expression together with the nature of the persistent inflammatory infiltrates are major contributors to the differences in clinical course between TMEV-IDD and R-EAE.

Epitope spreading is a process whereby epitopes distinct from and non-cross-reactive with an inducing epitope become major targets of an ongoing immune response. This phenomenon has been defined in experimental and natural situations as a consequence of acute or persistent infection and secondary to chronic tissue destruction that occurs during progressive autoimmune disease. We have investigated the functional significance of this process in the chronic stages of both autoimmune and virus-induced central nervous system (CNS) demyelinating disease models in the SJL/J mouse. During the relapsing-remitting course of experimental autoimmune encephalomyelitis (R-EAE) induced with defined encephalitogenic myelin peptides, CD4+ T cells specific for endogenous epitopes on both the initiating myelin protein (intramolecular epitope spreading) and distinct myelin proteins (intermolecular epitope spreading) are primed secondary to myelin destruction during acute disease and play a major functional role in mediating disease relapses. Similarly, epitope spreading to endogenous myelin epitopes appears to play a major functional role in the chronic-progressive course of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a virus-induced CD4+ T-cell-mediated immunopathology. In TMEV-IDD, myelin destruction is initiated by virus-specific CD4+ T cells which target virus epitopes persisting in CNS-derived antigen-presenting cells. However, the chronic stage of this progressive disease is associated with the activation of CD4+ T cells specific for multiple myelin epitopes. In both models, the temporal course of T-cell activation occurs in a hierarchical order of epitope dominance, spreading first to the most immunodominant epitope and progressing to lesser immunodominant epitopes. In addition, epitope spreading in R-EAE is regulated predominantly by CD28/B7-1 co-stimulatory interactions, as antagonism of B7-1-mediated co-stimulation using anti-B7-1 F(ab) fragments is an effective ameliorative therapy for ongoing disease. The process of epitope spreading has obvious important implications for the design of antigen-specific therapies for the treatment of autoimmune disease since these therapies will have to identify and target endogenous self epitopes associated with chronic tissue destruction.

Relapsing experimental autoimmune encephalomyelitis (R-EAE) is an immune-mediated demyelinating central nervous system (CNS) disease. Myeloablation and syngeneic bone marrow transplantation (SBMT), when performed at the peak of acute disease (day 14), prevented glial scarring and ameliorated the disease severity. In contrast, when syngeneic BMT was performed late in chronic phase (day 78), significant glial scarring remained and the clinical severity did not differ significantly from that of the controls. After SBMT in either the acute or chronic phase of disease, the posttransplant immune system remained responsive to myelin epitopes as determined by in vitro proliferation and interferon-gamma (IFN-gamma) production. However, in mice undergoing SBMT, in vivo delayed-type hypersensitivity (DTH) responses were significantly decreased while IFN-gamma RNA levels and inflammatory infiltrates within the CNS were slightly improved. We conclude that failure of SBMT to improve the clinical disease when performed in chronic phase may be due to preexisting glial scarring. We also conclude that in the absence of glial scarring and irreversible neuronal injury, in vivo DTH responses and histology are better predictors of clinical improvement than in vitro proliferation or IFN-gamma cytokine production.

Multiple sclerosis (MS) is a T cell-mediated autoimmune demyelinating disease, which may be initiated by a virus infection. Theiler's murine encephalomyelitis virus (TMEV), a natural mouse pathogen, is a picornavirus that induces a chronic, CD4+ T cell-mediated demyelinating disease with a clinical course and histopathology similar to that of chronic progressive MS (ref. 3). Demyelination in TMEV-infected mice is initiated by a mononuclear inflammatory response mediated by virus-specific CD4+ T cells targeting virus, which chronically persists in the CNS (ref. 4-6). We show that beginning 3-4 weeks after disease onset, T-cell responses to multiple myelin autoepitopes arise in an ordered progression and may play a pathologic role in chronic disease. Kinetic and functional studies show that T-cell responses to the immunodominant myelin proteolipid protein epitope (PLP139-151) did not arise because of cross-reactivity between TMEV and self epitopes (that is, molecular mimicry), but because of de novo priming of self-reactive T cells to sequestered autoantigens released secondary to virus-specific T cell-mediated demyelination (that is, epitope spreading). Epitope spreading is an important alternate mechanism to explain the etiology of virus-induced organ-specific autoimmune diseases.