Oral Janus kinase inhibitors for atopic dermatitis.

Atopic dermatitis (AD) is one of the most common inflammatory skin conditions. The pathogenesis of AD involves skin barrier disruption and immune activation of T-helper (TH)2 and TH22 and varying degrees of TH1 and TH17 activation in various patient subtypes. Although AD is mainly driven by TH2, the molecular and clinical heterogeneity of AD underscores the need for more efficacious treatments that target multiple immune axes. Janus kinase (JAK) inhibitors are novel therapeutics that broadly block many AD-related proinflammatory cytokines (interleukin [IL]-4, IL-5, IL-13, IL-31, thymic stromal lymphopoietin, interferon gamma, IL-12, IL-23, IL-17) across different immune pathways. Oral JAK inhibitors have been found to be efficacious in AD, with 2 (abrocitinib and upadacitinib) recently gaining US Food and Drug Administration approval and several others under investigation in clinical trials with promising results. These systemic agents have surpassed conventional thresholds of treatment response, with many patients achieving complete or almost complete skin clearance, and provide a fast-acting alternative therapy for patients who are not responsive to biologics or other conventional therapies. However, systemic JAK inhibitors come with health concerns, requiring additional long-term clinical trials to characterize their safety profile in patients with AD. This review summarizes the current literature on the safety and efficacy of oral JAK inhibitors in AD and discusses future directions for research.

Proteomic characterization of atopic dermatitis blood from infancy to adulthood.

BACKGROUND: Patients with atopic dermatitis (AD) have systemic biomarker dysregulation that differs by age group; however, the proteomic characteristics of these age-based changes are unknown. OBJECTIVE: To profile blood proteins of patients with AD across different age groups versus age-appropriate controls. METHODS: Using the Olink high-throughput proteomic platform, we profiled 375 serum proteins of 20 infants (age, 0-5 years), 39 children (age, 6-11 years), 21 adolescents (age, 12-17 years), and 20 adults (age, ≥18 years) with moderate-to-severe AD and 83 age-appropriate controls. RESULTS: Each group presented a distinct systemic proteomic signature. Th2-related proteins were increased in infant AD and further intensified with age through adolescence and adulthood (interleukin 4/CCL13/CCL17). In contrast, Th1 axis down-regulation was detected in infants with AD and gradually reversed to increased Th1 products (interferon γ/CXCL9/CXCL10/CCL2) in patients with AD from childhood to adulthood. Despite their short disease duration, infants already had evidence of systemic inflammation, with significant upregulation of innate immunity (interleukin 17C/ interleukin-1RN), T-cell activation/migration (CCL19), Th2 (CCL13/CCL17), and Th17 (PI3) proteins. Adults with AD present unique upregulation of cardiovascular proteins related to coagulation and diabetes. LIMITATIONS: Cross-sectional observational study with a single time point. CONCLUSION: Systemic immune signatures of AD are age-specific beyond the shared Th2 immune activation. These data advocate for precision medicine approaches based on age-specific AD profiles.

A phase 2a randomized vehicle-controlled multi-center study of the safety and efficacy of delgocitinib in subjects with moderate-to-severe alopecia areata.

Alopecia areata/AA is an autoimmune cause of nonscarring hair loss. The pathogenesis of AA involves many immune axes, including Th1/Th2 pathways. Delgocitinib is a pan-Janus kinase/JAK inhibitor that broadly blocks pro-inflammatory cytokines and has been effective in other inflammatory skin conditions. Recent human studies/reports have shown that use of some systemic JAK inhibitors led to hair regrowth, suggesting this medication class as a potential therapy for AA. However, topical treatment is desirable due to potential systemic side effects. To assess the efficacy and safety of topical delgocitinib in AA, we conducted a double-blind, randomized, vehicle-controlled clinical trial in 31 moderate-to-severe AA patients that were randomized 2:1 to receive delgocitinib ointment 30 mg/g (n = 20) or ointment vehicle (n = 11) for 12 weeks. The primary endpoint was change in severity of Alopecia Tool/SALT score from baseline to week 12. The secondary endpoint included safety profile by reported adverse events. Twenty-three subjects completed the trial, with eight discontinuing mostly due to voluntary withdrawal. Ten patients receiving delgocitinib ointment and three patients receiving vehicle showed SALT score improvements after 12 weeks, but the mean percent SALT improvement at week 12 compared to baseline between the two arms was not significant (p = 0.92). Our study suggests that delgocitinib ointment is not effective in moderate-to-severe AA, likely due to its inability to penetrate sufficiently deeply into the dermis of the scalp, but larger studies are necessary to assess whether a different formulation of topical JAK inhibitors may be suitable to treat mild or more localized forms of AA.

Transcriptomic Analysis of the Major Orphan Ichthyosis Subtypes Reveals Shared Immune and Barrier Signatures.

Preliminary work suggested upregulation of inflammatory pathways in patients with common forms of ichthyosis. However, a comprehensive characterization of skin from various ichthyosis subtypes is unavailable, precluding the development of targeted treatments. Thus, we sought to characterize the immune and barrier profiles of common and subtype-specific skin transcriptomes in a large group of patients with ichthyosis. We performed a global RNA-sequencing analysis in 54 patients with ichthyosis (7 with Netherton syndrome, 13 with epidermolytic ichthyosis, 16 with lamellar ichthyosis, and 18 with congenital ichthyosiform erythroderma) and 40 healthy controls. Differentially expressed genes were defined on the basis of fold changes > 2 and false discovery rate < 0.05 criteria. We found robust and significant T helper (Th) 22/Th17 skewing in all subtypes (e.g., IL-17A/C/F, S100A7/8/9/12; P < 0.001) with modest changes in Th2 pathway, primarily in Netherton syndrome, and Th1 skewing in congenital ichthyosiform erythroderma. Across all subtypes (less evident in epidermolytic ichthyosis), lipid metabolism and barrier junction markers were downregulated (e.g., FA2H, CDH10/11/12/2; P < 0.05), whereas epidermal cornification and proliferation measures were upregulated (e.g., SPRR1A/1B/2C/2G, EREG; P < 0.05). Our findings suggest that the common ichthyosis variants share aberrations in Th17/Th22 and barrier function, with minimal Th2 modulation. This may help to elucidate the pathogeneses of these subtypes and inform the development of subtype-specific treatments.

COVID-19 Symptoms Are Attenuated in Moderate-to-Severe Atopic Dermatitis Patients Treated with Dupilumab.

BACKGROUND: In the SARS-CoV-2/COVID-19 pandemic, we need to understand the impact of immunomodulatory medications on COVID-19 symptom severity in patients with inflammatory diseases, including the type 2/Th2 polarized skin disease, atopic dermatitis (AD). OBJECTIVE: Because it is believed that type 1/Th1 immunity controls viral infections and that there is a Th1/Th2 counter-regulation, we hypothesized that Th2 targeting with the IL-4Rα-antagonist, dupilumab, in patients with moderate-to-severe AD would rebalance the Th1/Th2 axis, potentially leading to attenuated COVID-19 symptoms. METHODS: A total of 1237 patients with moderate-to-severe AD in the Icahn School of Medicine at Mount Sinai Department of Dermatology were enrolled in a registry. Patients were screened for COVID-19-related symptoms and assigned a severity score (asymptomatic [0]-fatal [5]). Scores were compared among 3 treatment groups: dupilumab (n = 632), other systemic treatments (n = 107), and limited/no treatment (n = 498). Demographic and comorbid covariates were adjusted by multivariate generalized logistic regression models. RESULTS: The dupilumab-treated group showed reduced incidence and severity of COVID-19 symptoms versus other treatment groups. Dupilumab-treated patients were less likely to experience moderate-to-severe symptoms versus patients on other systemics (P = .01) and on limited/no treatment (P = .04), and less likely to experience any symptoms versus patients on other systemics (P = .01). This effect was seen in our entire cohort and in the subgroup of patients with verified COVID-19 or high-risk exposure. CONCLUSIONS: Patients on dupilumab experienced less severe COVID-19 manifestations and lesser symptoms compared with patients on other systemics and on limited/no treatment. These results suggest that Th2 modulation with dupilumab may have a protective effect on anti-viral immune response in patients with AD.

Transcriptomic Profiling of Tape-Strips From Moderate to Severe Atopic Dermatitis Patients Treated With Dupilumab.

BACKGROUND: Tape-strips are a minimally invasive approach to characterize skin biomarkers in atopic dermatitis (AD). However, they have not yet been used for tracking gene expression changes with systemic treatment. OBJECTIVE: The aim of the study was to evaluate gene expression changes and therapeutic response biomarkers in AD patients before and after dupilumab (interleukin 4Rα antibody) treatment using tape-strips to obtain epidermal tissue for analysis. METHODS: Lesional and nonlesional tape-stripped skin was sampled from 18 AD patients before and after dupilumab treatment and from 17 healthy subjects and analyzed by RNA-seq. RESULTS: At baseline, we detected 6745 and 4859 differentially expressed genes between lesional and nonlesional skin versus normal, respectively, whereas 841 and 977 genes were differentially expressed after treatment, respectively (fold change >1.5 and false discovery rate <0.05). Tape-strips captured significant modulation with dupilumab in key AD immune (eg, C-C motif chemokine ligand 13 [CCL13], CCL17, CCL18) and barrier (eg, periplakin, FA2H) biomarkers. Changes in biomarkers (CCL20, interleukin 34, FABP7) were also significantly correlated with clinical disease improvements (Eczema Area and Severity Index; R > 0.5 or R < -0.4, P < 0.05). CONCLUSIONS: This real-life study represents the first comprehensive RNA-seq molecular profiling of tape-strips from moderate to severe AD patients after dupilumab therapy. Analysis of tape strip specimens detected significant gene expression changes in key AD biomarkers with dupilumab treatment, suggesting that this approach may be useful to monitor therapeutic responses in inflammatory skin diseases.

Proteomic signatures of inflammatory skin diseases: a focus on atopic dermatitis.

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by cutaneous and systemic inflammation and barrier abnormalities. Over the past few decades, proteomic studies have been increasingly applied to AD research to compliment transcriptomic evaluations. Proteomic analyses helped identify new biomarkers of AD, allowing investigation of both the cutaneous AD profile and the systemic inflammation associated with the disease.Areas covered: This review discusses key studies that utilized various proteomic technologies to analyze AD skin and/or blood, which facilitated discovery of biomarkers related to pathogenesis, disease severity, systemic inflammation, and therapeutic response. Moreover, this review summarizes proteomic studies that helped define various AD endotypes/phenotypes. A literature search was conducted by querying Scopus, Google Scholar, PubMed/Medline, and Clinicaltrials.gov up to January 2021.Expert opinion: Use of proteomics in AD has allowed for identification of novel AD-related protein biomarkers. This approach continues to evolve and is becoming increasingly common for the study of AD, in conjunction with other -omics platforms, as proteomics shifts to quicker and more sensitive methods for detection of potential protein biomarkers. Although many biomarkers have been identified thus far, future larger studies are necessary to further correlate these markers with clinical parameters.

A Sleep Hygiene Intervention to Improve Sleep Quality for Hospitalized Patients.

INTRODUCTION: Poor sleep is a pervasive problem for hospitalized patients and can contribute to adverse health outcomes. METHODS: We aimed to improve self-reported sleep for patients on a general medicine ward as measured by the Richards-Campbell Sleep Questionnaire (RCSQ) as well as the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) question addressing quietness at night. We utilized a non-pharmacologic sleep hygiene bundle composed of a short script with sleep hygiene prompts, such as whether patients would like the shades closed or the lights turned off, as well as a sleep package including an eye mask, earplugs, lavender scent pad, and non-caffeinated tea. Relaxing music was played at bedtime and signs promoting the importance of quietness at night were placed around the unit. Front-line champions were identified to aid with implementation. RESULTS: A total of 931 patients received the intervention. In a sample of surveyed patients, we observed an increase in the RCSQ global score from 6.0 (IQR 3.0-7.0) to 6.2 (IQR 4.0-7.8) from the pre- to post- intervention periods (p = 0.041), as well as increases in three of the five individual survey components. Additionally, HCAHPS "quietness at night" score increased on the unit from 34.1% pre-intervention to 42.5% post-intervention. CONCLUSION: A nonpharmacologic sleep hygiene protocol paired with provider education and use of champions was associated with modest improvements in patients' perceived sleep and unit HCAHPS scores.

Systemic Psoriasis Therapies and Comorbid Disease in Patients with Psoriasis: A Review of Potential Risks and Benefits.

Psoriasis is an inflammatory skin disease that is associated with many comorbidities. Several psoriasis treatments approved by the United States Food and Drug Administration have been shown to have beneficial effects on these comorbidities, while others might lead to an exacerbation of these conditions. In this article, we review studies of psoriasis treatments and their level of evidence for use in co-occurring diseases. An awareness of the multifaceted effects of certain psoriasis medications can enable physicians to provide more personalized treatment to their most complicated patients.

A randomized placebo-controlled single-center pilot study of the safety and efficacy of apremilast in subjects with moderate-to-severe alopecia areata.

Alopecia areata (AA) is a common autoimmune disease that results in non-scarring hair loss. AA pathogenesis is thought to involve multiple inflammatory cytokines. Apremilast is a phosphodiesterase 4 (PDE4) inhibitor that reduces pro-inflammatory cytokine production. Recent studies demonstrate upregulation of PDE4 in human scalp lesions of AA patients and hair regrowth in a humanized AA mouse model upon apremilast treatment, suggesting a possible potential of apremilast in AA. To assess the efficacy and safety of apremilast in AA, we conducted a double-blind, placebo-controlled single-center pilot study in 30 moderate-to-severe AA patients (≥ 50% scalp involvement) that were randomized 2:1 to receive apremilast (n = 20) or placebo (n = 10) orally for 24 weeks. The primary endpoint was the percentage of patients achieving 50% reduction in severity of alopecia tool (SALT) score (SALT50) at 24 weeks compared to baseline, and the secondary endpoints included the percent change in SALT score at weeks 24 and 48. Eight patients in the apremilast arm withdrew prior to week 24 along with two patients in the placebo group, mostly due to lack of efficacy and adverse events. At 24 weeks, only 1 of 12 apremilast-treated subjects achieved SALT50, and similarly 1 of 8 placebo-treated subjects achieved SALT50. The difference between the mean percent improvement in SALT score at week 24 compared to baseline of the two study arms was not statistically significant (p = 0.38). The lack of treatment response in most of our patients argues against a pathogenic role for PDE4 specifically in moderate-to-severe AA, but targeting this pathway may still be of value in patients with mild AA as there is less of an inflammatory burden in this population. However, future larger studies may be needed to conclude apremilast's lack of efficacy in moderate-to-severe AA.

Common allergens present in personal care products: identification, diagnosis, and management.

The incidence of allergic contact dermatitis (ACD) reactions to personal care products has progressively increased, affecting women more so than men. Fragrances and preservatives are the major sensitizers behind cosmetic-induced ACD, due to their ubiquitous presence in these products, though emulsifiers, ultraviolet filters, and botanical allergens have been implicated as well. While patch testing is the standard for diagnosing ACD, many cosmetic-specific antigens are not currently included within the commercially available kits. Therefore, patch testing for potential cosmetic-induced ACD should be supplemented with additional compounds commonly found in personal use products. Effective treatment of ACD must involve accurate identification and removal of the offending agent.

Moisturizers: A Comparison Based on Allergens and Economic Value.

BACKGROUND: The economic burden of cosmetics, such as moisturizers, has been increasing. Despite the high price of some market moisturizers, there have been no studies evaluating the allergenicity of these products. OBJECTIVE: The aim of this study was to evaluate the potential allergens within moisturizers based on economic value, by analyzing the substances found in moisturizers available online at the largest drugstore chain-CVS Health (CVS Health, Woonsocket, RI). METHODS: In this cross-sectional study, ingredients found in 50 expensive and 50 inexpensive moisturizers were matched with sensitizers within the Core Allergen Series published by the American Contact Dermatitis Society and the North American Contact Dermatitis Group. Student t test was used to compare the mean number of allergens present in each group. A χ test or Fisher exact test, where necessary, was used to compare the rates of specific allergen groups between the expensive and inexpensive products. RESULTS: Twenty-six allergenic substances were present overall in the 100 total products surveyed. The expensive moisturizers averaged significantly more allergens per product (8.28 vs 5.60, P = 0.003) than the inexpensive products. CONCLUSIONS: The sensitizing potential of expensive moisturizers may be higher than that of inexpensive moisturizers. Physicians may counsel cosmetic-induced allergic contact dermatitis (ACD) patients that monetary value is not a suitable proxy for evaluating the risk of ACD.