Targeting the Aryl Hydrocarbon Receptor to Address the Challenges of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic relapsing–remitting disease with a multifactorial etiology involving epidermal barrier and immunologic dysfunction. Topical therapies form the mainstay of AD treatment, but options are limited by adverse effects and restrictions on application site, duration, and extent of use. Tapinarof (VTAMA; Dermavant Sciences, Inc.) is a first-in-class, non-steroidal, topical aryl hydrocarbon receptor (AhR) agonist approved for the treatment of plaque psoriasis. AhR is a ligand-dependent transcription factor with wide-ranging roles, including regulation of homeostasis and immune response in skin cells. AhR expression and signaling are altered in many inflammatory skin diseases, and clinical trials with tapinarof have validated AhR as a therapeutic target capable of delivering significant efficacy. Tapinarof cream 1% once daily demonstrated efficacy versus vehicle in adults and adolescents with AD and is being investigated in the ADORING trials for the treatment of AD in adults and children down to 2 years of age. J Drugs Dermatol. 2024;23(2):23-28.  doi:10.36849/JDD.8026.

Atopic Dermatitis Polypharmacy and Out-Of-Pocket Healthcare Expenses.

BACKGROUND: Atopic dermatitis (AD) out-of-pocket (OOP) expenses are substantial and impact household finances. Prescription polypharmacy and its association with OOP expenses in AD is poorly understood. OBJECTIVE: To characterize prescription polypharmacy and its association with OOP healthcare expenses among individuals with AD. METHODS: An online survey was administered to National Eczema Association members (N=113,502). Inclusion criteria (US resident, age ≥18, self-reported or caregiver of individual with AD) was met by 77.3% (1,118/1,447) of respondents. RESULTS: Polypharmacy (≥5 prescription treatments for AD in the past year) was associated with increased AD severity, poorer control, increased flares, increased healthcare provider visits, and comorbid asthma, allergic rhinitis, food allergy, and skin infections (P≤0.01). Polypharmacy noted with all prescription therapies was most associated with biologic (dupilumab), oral immunosuppressant (azathioprine, cyclosporine, methotrexate, corticosteroids), oral antimicrobial, and topical calcineurin inhibitor (P≤0.0005) use. Respondents with polypharmacy had increased OOP expenditures across numerous categories, including office visit co-pays, prescription medications both covered and not covered by insurance, hospitalization, emergency room visits, mental health services, non-prescription health products such as sleep aids, analgesics, and supplements, and alternative medications (P<0.005). Individuals with polypharmacy had elevated yearly OOP expenses (median [range]: $1200 [$0-$200,000]), higher monthly OOP costs than average, and more harmful household financial impact (P<0.0001 for all). CONCLUSION: Individuals with AD report considerable polypharmacy, which is associated with increased OOP expenses and harmful financial impact. Strategies are needed to reduce polypharmacy, minimize OOP costs, and optimize clinical outcomes. J Drugs Dermatol. 2023;22(2): doi:10.36849/JDD.7038.

Consensus Statements on the Use of Corticosteroid-Containing Topical Medications in Psoriasis.

This article aims to provide consensus statements on the use of corticosteroid-containing topical medications for the management of psoriasis. This Psoriasis Expert Group (PEG) includes dermatologist voting members with expertise in psoriasis who convened and evaluated the use of topical medications and previously published guidelines. A modified Delphi process was conducted to reach consensus results. Two rounds of voting were conducted for each topic and panel consensus was determined.  Nine statements were developed regarding topical medication efficacy, patient quality of life, frequency of application, medication "feel", and safety and tolerability. Dermatologist experts voted on the statements separately. Patients were not polled. All items received agreement: 15 with high consensus and 1 with moderate consensus.  For the treatment of psoriasis, the PEG agreed that patients and physicians prefer topical medications that are effective, provide long-lasting results, have a quick onset of action, and "feel good on the skin" with few adverse effects. The developed consensus statements provide guidance on the topical treatment of psoriasis, including combination therapies, such as a vitamin D and topical corticosteroid analog. These recommendations will be continuously reviewed and updated as more evidence continues to emerge.  April W. Armstrong AW, Reddy R, Khan S, et al. Consensus statements on the use of corticosteroid-containing topical medications in psoriasis. J Drugs Dermatol. 2023;22(8):736-741. doi:10.36849/JDD.7453.

DESCRIBE-AD: A novel classification framework for atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic, inflammatory skin disease associated with heterogeneous morphology, distribution, symptoms, severity, extent, longitudinal courses, quality of life burden, comorbidities, and treatment responses. This heterogeneity contributes to challenges in diagnosis, the characterization of disease activity, and therapeutic stratification. OBJECTIVE: To develop a framework to standardize AD assessment. METHODS: We propose a novel framework to assess AD based on a literature review and clinical experience. RESULTS: DESCRIBE-AD is a framework that can effectively capture the clinical domains contributing to AD heterogeneity and includes both patient- and clinician-reported perspectives. DESCRIBE-AD includes assessments of Dermatitis morphology and phenotype, Evolution of disease, Symptom severity, Comorbid health disorders, Response to therapy, Intensity of lesions, Burden of disease, and Extent of lesions. Rather than placing the focus on any single, specific aspect of AD, DESCRIBE-AD allows for a comprehensive approach to the assessment and clinical management of AD. CONCLUSIONS: DESCRIBE-AD is a novel framework that can be used to better describe the heterogeneity of AD and guide treatment decisions.

Stress, inflammation, and defense of homeostasis.

Inflammation is traditionally considered a defense response induced by infection or injury. However, inflammation can also be induced by tissue stress and malfunction in the absence of infection or overt tissue damage. Here we discuss the relationship between homeostasis, stress responses, and inflammation. Stress responses have cell-autonomous and cell-extrinsic components, the latter contributing to tissue level adaptation to stress conditions. Inflammation can be thought of as the extreme end of a spectrum that ranges from homeostasis to stress response to bona fide inflammatory response. Inflammation can be triggered by two types of stimuli: extreme deviations of homeostasis or challenges that cause a disruption of homeostasis. This perspective may help to explain qualitative differences and functional outcomes of diverse inflammatory responses.

JAK inhibitors in the treatment of atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder associated with heterogenous presentation and often immense patient burden. Safe, targeted treatment options are currently limited. This focused review of the published literature, including clinical trial results, case reports, and abstracts, as well as presentations from scientific meetings and data from industry press releases, describes the use of topical and systemic Janus kinase (JAK) inhibitors in the treatment of AD. New topical JAK inhibitors include ruxolitinib (JAK1/2) and delgocitinib (pan-JAK). Ruxolitinib cream met all primary and secondary endpoints in phase 3 clinical trials for mild-to-moderate AD with minimal treatment-emergent adverse events. Delgocitinib ointment was recently approved in Japan for pediatric and adult AD. Oral JAK inhibitors include baricitinib (JAK1/2), abrocitinib (JAK1-selective), and upadacitinib (JAK1-selective). All 3 met primary and secondary endpoints across numerous trials for moderate-to-severe AD. Treatment-emergent adverse events were mainly mild to moderate and included acne, nausea, headache, upper respiratory tract infection, and to a lesser degree, herpes infection and selected laboratory abnormalities. JAK inhibitors hold great promise as the next generation of targeted AD therapy. While their outstanding efficacy is balanced by a favorable safety profile in clinical trials, real-world data are needed to better understand long-term safety, durability, and treatment success.

New treatments in atopic dermatitis.

OBJECTIVE: To discuss the efficacy and safety of novel and emerging topical and systemic therapeutic agents for atopic dermatitis (AD). DATA SOURCES: The review of the published literature was performed using the PubMed database, published abstracts and virtual presentations from scientific meetings, posted results on ClinicalTrials.gov, and data from industry press releases. STUDY SELECTIONS: Primary manuscripts with trial results, case reports, case series, clinical trial data from ClinicalTrials.gov, and articles highlighting expert perspectives on management of AD were selected. RESULTS: Emerging topical and systemic therapies primarily target the type 2 immune pathway. Moreover, 2 newer targeted medications are now approved by the Food and Drug Administration for both children and adults, crisaborole 2% ointment and dupilumab, with several others in the therapeutic pipeline. New directions in developing topical medications include Janus kinase inhibitors, tapinarof (an aryl hydrocarbon receptor agonist), and agents to correct microbial dysbiosis. In addition to the subcutaneously injected monoclonal antibody targeting the interleukin (IL) 4 receptor (dupilumab), other biologics targeting IL-13, IL-31, IL-33, OX40, and thymic stromal lymphopoietin are currently being tested. Oral Janus kinase inhibitors are showing outstanding efficacy and no serious safety signs, but safety concerns remain. CONCLUSION: Given the tremendous burden of AD on physical, mental, and social health, the need is high to develop new, targeted therapies. Advances in our understanding of AD pathogenesis have paved the way toward the development of new therapies that promise to revolutionize our management of AD. Future research will focus on long-term efficacy and safety and creating predictive models for choosing best management options on a personalized basis.

Clinical phenotyping of atopic dermatitis using combined itch and lesional severity: A prospective observational study.

BACKGROUND: Patients with atopic dermatitis (AD) have heterogeneous clinical phenotypes, including different combinations of itch and lesional severity. Little is known about the characteristics and course of these subtypes. OBJECTIVE: To determine the characteristics, associations, burden, and course of patients with AD using combined itch and lesional severity. METHODS: A prospective practice-based study was performed using questionnaires and physical examination (n=592). AD subsets were defined using verbal rating scale for average itch combined with either eczema area and severity index, objective-scoring atopic dermatitis (SCORAD), or validated investigator's global assessment as follows: mild-moderate itch and lesions (MI-ML), mild-moderate itch and severe lesions (MI-SL), severe itch and mild-moderate lesions (SI-ML), and severe itch and lesions (SI-SL). RESULTS: At baseline, there were only weak-moderate correlations of numerical rating scales for worst itch or average itch or SCORAD itch with eczema area and severity index, objective-SCORAD, body surface area, and validated investigator's global assessment (Spearman's rho = 0.32-0.62). Most patients had MI-ML (59.4%-62.3%), followed by SI-ML (21.3%-29.1%), SI-SL (6.0%-12.9%), and MI-SL (3.8%-6.4%). Patients with SI-SL, followed by SI-ML and MI-SL, described their AD as being more severe overall and had worse impairment in sleep, mental health, and quality of life. However, those with MI-SL or SI-SL were far more likely to be classified as severe by a physician (multivariable logistic and linear regression, P < .005 for all). Baseline MI-SL, SI-ML, and SI-SL were associated with similar longitudinal courses over time and more AD flares and itch triggers than MI-ML. CONCLUSION: Combined itch and lesional severity seem to describe unique AD phenotypes. Further studies are needed to confirm these findings and understand the optimal treatments for these groups.

Association of herpes zoster and chronic inflammatory skin disease in US inpatients.

BACKGROUND: Patients with chronic inflammatory skin disease (CISD) have potential risk factors for herpes zoster (HZ). However, little is known about HZ risk in CISD. OBJECTIVE: To determine whether CISD is associated with HZ. METHODS: Data were analyzed from the 2002 to 2012 Nationwide Inpatient Sample, a representative cohort of US hospitalizations (N = 68,088,221 children and adults). RESULTS: In multivariable logistic regression models including age, sex, race/ethnicity, insurance, household income, and long-term systemic corticosteroid use, hospitalization for HZ was associated with atopic dermatitis (adjusted odds ratio [95% confidence interval], 1.38 [1.14-1.68]), psoriasis (4.78 [2.83-8.08]), pemphigus (1.77 [1.01-3.12]), bullous pemphigoid (1.77 [1.01-3.12]), mycosis fungoides (3.79 [2.55-5.65]), dermatomyositis (7.31 [5.27-10.12]), systemic sclerosis (1.92 [1.47-2.53]), cutaneous lupus erythematosus (1.94 [1.10-3.44]), vitiligo (2.00 [1.04-3.85]), and sarcoidosis (1.52 [1.22-1.90]). Only lichen planus (crude odds ratio [95% confidence interval], 3.01 [1.36-6.67]), Sézary syndrome (12.14 [5.20-28.31]), morphea (2.74 [1.36-5.51]), and pyoderma gangrenosum (2.44 [1.16-5.13]) showed increased odds in bivariable models. Sensitivity analyses among those younger than 60 and younger than 50 years showed similar results. Predictors of HZ in CISD included female sex, fewer chronic conditions, and long-term systemic corticosteroid use. LIMITATIONS: Cross-sectional study. CONCLUSIONS: Many CISDs are associated with increased hospitalization for HZ, even below the ages recommended for HZ vaccination. Additional studies are needed to establish CISD-specific vaccination guidelines.

Atopic Dermatitis (Eczema).

This JAMA Patient Page describes atopic dermatitis (eczema) and its symptoms and treatment options.

Taking It Back to Basics: Re-emphasizing the Role of Moisturization in Atopic Dermatitis.

Atopic dermatitis (AD) is a common, burdensome inflammatory skin disease. In recent years, multiple safe and effective monotherapy treatments directly targeting immune dysregulation in AD have been approved and integrated into clinical practice. Although the etiopathogenesis of AD is complex, it is widely recognized that alongside immune dysregulation, skin barrier disruption also plays an essential role in disease pathophysiology. For this reason, regular moisturization has been a foundational mainstay of therapy, consistently recommended by treatment guidelines regardless of disease severity or therapeutic approach. It is vital for healthcare providers to continuously educate patients and caregivers about the importance of optimizing skin barrier function by maintaining proper moisturization as part of their treatment plan and help them make data-driven decisions to navigate the wide array of available products.

More yeast, more problems?: reevaluating the role of Malassezia in seborrheic dermatitis.

Seborrheic dermatitis (SD) is an inflammatory skin disorder and eczema subtype increasingly recognized to be associated with significant physical, psychosocial, and financial burden. The full spectrum of SD, including dandruff localized to the scalp, is estimated to affect half of the world's population. Despite such high prevalence, the exact etiopathogenesis of SD remains unclear. Historically, many researchers have theorized a central, causative role of Malassezia spp. based on prior studies including the proliferation of Malassezia yeast on lesional skin of some SD patients and empiric clinical response to antifungal therapy. However, upon closer examination, many of these findings have not been reproducible nor consistent. Emerging data from novel, targeted anti-inflammatory therapeutics, as well as evidence from genome-wide association studies and murine models, should prompt a reevaluation of the popular yeast-centered hypothesis. Here, through focused review of the literature, including laboratory studies, clinical trials, and expert consensus, we examine and synthesize the data arguing for and against a primary role for Malassezia in SD. We propose an expansion of SD pathogenesis and suggest reframing our view of SD to be based primarily on dysregulation of the host immune system and skin epidermal barrier, like other eczemas.

Dupilumab as Add-on Therapy for Management of Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is characterized by pruritus, urticaria and associated with substantial patient burden. Emerging clinical trial data suggest dupilumab, an anti-IL-4Rα biologic indicated for several Type-2 inflammatory diseases, may have clinical utility for CSU. Here we present real world clinical data evaluating dupilumab as add-on therapy for CSU. We queried our tertiary academic center electronic health record for all patients with an ICD-9/10 code for urticaria with a history of dupilumab use (1/1/2010-6/30/2022). Retrospective chart review was performed to confirm CSU diagnosis, dupilumab use, patient demographics, medical history, treatments, and outcomes. Data were evaluated using summary and descriptive statistics, paired t-test, and Fisher's exact test. A total of 199 patients were identified: 39 had active CSU at time dupilumab initiation; six were excluded due to limited follow up. The most common indication for dupilumab prescription was atopic dermatitis (57.6%), followed by asthma (27.3%). Mean length of dupilumab therapy was 23 months. Following dupilumab, there was a significant reduction in number of patients on daily H1 antagonists (pre: 27 [81.8%]; post: 20 (60.1%); p=0.03), as well as total daily number of antihistamines (pre: 1.95±2.0; post: 0.13±0.2; p=0.01). For patients with moderate/severe vs. mild disease, there was greater improvement in disease control as assessed by physicians global impression of change (77% vs. 30%, p=0.02). In this real-world study, when used as add-on therapy for patients with CSU, dupilumab was associated with improved disease control and decreased H1 blocker use, suggesting a future for dupilumab as an approvedbiologic therapy for the treatment of CSU.

Evaluating Access to Prescription Medications in the Atopic Dermatitis Patient Population in the USA.

INTRODUCTION: Despite advances in atopic dermatitis (AD) treatments, many patients face challenges obtaining medications. This study aimed to determine the frequency and causes of insurance coverage delays and denials for AD prescriptions and characterize the associated wait times and extent to which patients understand what to do when faced with a coverage issue. METHODS: This was a cross-sectional, observational study in which adult U.S. residents (aged 18+ years) with AD or caregivers of pediatric U.S. patients with AD (aged 0-17 years) completed an online survey (3 June-16 July 2021). RESULTS: Respondents (N = 978) were primarily adults with AD (81.8%), female (67.7%), and white (70.2%). There were 645 insurance delays or denials for AD prescriptions, with 48.1% (470/978) of respondents experiencing at least one delay/denial in the past year. Most delays/denials were for topical steroids (39.2%, 253/645), the most highly used prescription treatment class (83.9%, 821/978). However, the highest rate of delay/denials was for biologics, of which 43.6% (109/250) of all prescriptions faced a delay or denial. Denials were caused primarily by step therapy (27.6%) and delays by prior authorization (55.1%). Only 56.0% of respondents said they would know what to do if they faced an issue with AD prescription coverage. CONCLUSIONS: Patients with AD frequently experience insurance-related barriers to obtaining recommended therapies, and many do not know how to respond when these barriers arise. Strategies to improve timely therapeutic access are needed.