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American Journal of Clinical Dermatology Sep 2022Atopic dermatitis (AD) is a chronic inflammatory skin condition that can have tremendous impact on quality of life for affected children and adults. First-line therapy... (Review)
Review
Atopic dermatitis (AD) is a chronic inflammatory skin condition that can have tremendous impact on quality of life for affected children and adults. First-line therapy for acute management of AD includes topical therapies such as corticosteroids, calcineurin inhibitors, and, more recently, the phosphodiesterase inhibitor crisaborole. Topical agents have remained the mainstay therapy for decades; however, there has been a longstanding need for topical therapies with high efficacy and low risk of adverse effects with long-term use. Given the ongoing advances in understanding the pathogenesis of AD, there are novel targets for pharmacological intervention. We are now in an unprecedented time with more than 40 topical treatments in the pipeline for AD in addition to many developments and treatments on the horizon. This review summarizes selected therapeutic topical agents in later phases of development that target various aspects in the pathogenesis of AD such as Janus kinase inhibition (ruxolitinib and delgocitinib), phosphodiesterase-4 inhibition (roflumilast and difamilast), aryl hydrocarbon modulation (tapinarof), and modulation of the microbiome. We also review novel targeted therapies that are in early phase clinical trials, including AMTX-100, BEN-2293, and PRN473. Preliminary findings on efficacy and tolerability of most of these agents are promising, but further studies are warranted to evaluate the long-term safety and efficacy of these novel agents against the current standard of care.
Topics: Administration, Topical; Adult; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Quality of Life
PubMed: 36048410
DOI: 10.1007/s40257-022-00712-0 -
British Journal of Pharmacology May 2023Atopic dermatitis is a common chronic pruritic inflammatory disease of the skin involving neuro-immune communication. Neuronal mechanism-based therapeutic treatments...
BACKGROUND AND PURPOSE
Atopic dermatitis is a common chronic pruritic inflammatory disease of the skin involving neuro-immune communication. Neuronal mechanism-based therapeutic treatments remain lacking. We investigated the efficacy of intravenous lidocaine therapy on atopic dermatitis and the underlying neuro-immune mechanism.
EXPERIMENTAL APPROACH
Pharmacological intervention, immunofluorescence, RNA-sequencing, genetic modification and immunoassay were performed to dissect the neuro-immune basis of itch and inflammation in atopic dermatitis-like mouse model and in patients.
KEY RESULTS
Lidocaine alleviated skin lesions and itch in both atopic dermatitis patients and calcipotriol (MC903)-induced atopic dermatitis model by blocking subpopulation of sensory neurons. QX-314, a charged Na blocker that enters through pathologically activated large-pore ion channels and selectivity inhibits a subpopulation of sensory neurons, has the same effects as lidocaine in atopic dermatitis model. Genetic silencing Na 1.8-expressing sensory neurons was sufficient to restrict cutaneous inflammation and itch in the atopic dermatitis model. However, pharmacological blockade of TRPV1-positive nociceptors only abolished persistent itch but did not affect skin inflammation in the atopic dermatitis model, indicating a difference between sensory neuronal modulation of skin inflammation and itch. Inhibition of activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons by lidocaine largely accounts for the therapeutic effect of lidocaine in the atopic dermatitis model.
CONCLUSION AND IMPLICATIONS
Na 1.8 sensory neurons play a critical role in pathogenesis of atopic dermatitis and lidocaine is a potential anti-inflammatory and anti-pruritic agent for atopic dermatitis. A dissociable difference for sensory neuronal modulation of skin inflammation and itch contributes to further understanding of pathogenesis in atopic dermatitis.
Topics: Mice; Animals; Dermatitis, Atopic; Pruritus; Skin; Inflammation; Sensory Receptor Cells
PubMed: 36521846
DOI: 10.1111/bph.16012 -
International Journal of... 2022We investigated whether purpurin inhibits various pathways of inflammation leading to atopic dermatitis.
OBJECTIVE
We investigated whether purpurin inhibits various pathways of inflammation leading to atopic dermatitis.
INTRODUCTION
1,2,4-Trihydroxyanthraquinone, commonly called purpurin, is an anthraquinone that is a naturally occurring red/yellow dye. Purpurin is a highly antioxidative anthraquinone and previous studies have reported antibacterial, anti-tumor, and anti-oxidation activities in cells and animals. However, the skin inflammatory inhibition activity mechanism study of purpurin has not been elucidated in vitro.
METHODS
In this study, we investigated the anti-inflammatory activity of purpurin in HaCaT (human keratinocyte) cell lines stimulated with a mixture of tumor necrosis factor-alpha (TNF-α)/Interferon-gamma (IFN-γ). The inhibitory effect of Purpurin on cytokines (IL-6, IL-8, and IL-1β) and chemokine (TARC, MDC, and RANTES) was confirmed by ELISA and RT-qPCR. We investigated each signaling pathway and the action of inhibitors through western blots.
RESULTS
The expression levels of cytokines and chemokines were dose-dependently suppressed by purpurin treatment in TNF-α/IFN-γ-induced HaCaT cells from ELISA and real-time PCR. Purpurin also inhibited protein kinase B (AKT), mitogen-activated protein kinase (MAPKs), and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) activation in TNF-α/IFN-γ-stimulated HaCaT cells. Additionally, there was a synergistic effect when purpurin and inhibitor were applied together, and inflammation was dramatically reduced.
CONCLUSION
Therefore, these results demonstrate that purpurin exhibits anti-inflammatory and anti-atopic dermatitis activity in HaCaT cells.
Topics: Animals; Anthraquinones; Cytokines; Dermatitis, Atopic; HaCaT Cells; Humans; Inflammation; Interferon-gamma; Tumor Necrosis Factor-alpha
PubMed: 35794850
DOI: 10.1177/03946320221111135 -
The Journal of Investigative Dermatology Aug 2023Immunologically targeted therapies have revolutionized the treatment of inflammatory dermatoses, including atopic dermatitis and psoriasis. Although immunologic... (Review)
Review
Immunologically targeted therapies have revolutionized the treatment of inflammatory dermatoses, including atopic dermatitis and psoriasis. Although immunologic biomarkers hold great promise for personalized classification of skin disease and tailored therapy selection, there are no approved or widely used approaches for this in dermatology. This review summarizes the translational immunologic approaches to measuring treatment-relevant biomarkers in inflammatory skin conditions. Tape strip profiling, microneedle-based biomarker patches, molecular profiling from epidermal curettage, RNA in situ hybridization tissue staining, and single-cell RNA sequencing have been described. We discuss the advantages and limitations of each and open questions for the future of personalized medicine in inflammatory skin disease.
Topics: Humans; Dermatitis, Atopic; Precision Medicine; Dermatology; Psoriasis; Skin Diseases; Biomarkers
PubMed: 37341663
DOI: 10.1016/j.jid.2023.04.005 -
Allergy Apr 2023The effectiveness of emollients for preventing atopic dermatitis/eczema is controversial. The Barrier Enhancement for Eczema Prevention trial evaluated the effects of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The effectiveness of emollients for preventing atopic dermatitis/eczema is controversial. The Barrier Enhancement for Eczema Prevention trial evaluated the effects of daily emollients during the first year of life on atopic dermatitis and atopic conditions to age 5 years.
METHODS
1394 term infants with a family history of atopic disease were randomized (1:1) to daily emollient plus standard skin-care advice (693 emollient group) or standard skin-care advice alone (701 controls). Long-term follow-up at ages 3, 4 and 5 years was via parental questionnaires. Main outcomes were parental report of a clinical diagnosis of atopic dermatitis and food allergy.
RESULTS
Parents reported more frequent moisturizer application in the emollient group through to 5 years. A clinical diagnosis of atopic dermatitis between 12 and 60 months was reported for 188/608 (31%) in the emollient group and 178/631 (28%) in the control group (adjusted relative risk 1.10, 95% confidence interval 0.93 to 1.30). Although more parents in the emollient group reported food reactions in the previous year at 3 and 4 years, cumulative incidence of doctor-diagnosed food allergy by 5 years was similar between groups (92/609 [15%] emollients and 87/632 [14%] controls, adjusted relative risk 1.11, 95% confidence interval 0.84 to 1.45). Findings were similar for cumulative incidence of asthma and hay fever.
CONCLUSIONS
Daily emollient application during the first year of life does not prevent atopic dermatitis, food allergy, asthma or hay fever.
Topics: Infant; Humans; Child, Preschool; Dermatitis, Atopic; Emollients; Rhinitis, Allergic, Seasonal; Food Hypersensitivity; Asthma; Eczema; Treatment Outcome
PubMed: 36263451
DOI: 10.1111/all.15555 -
The Journal of Allergy and Clinical... Aug 2022Few studies have analyzed the blood transcriptome in atopic dermatitis (AD).
BACKGROUND
Few studies have analyzed the blood transcriptome in atopic dermatitis (AD).
OBJECTIVE
We explored blood transcriptomic features of moderate to severe AD.
METHODS
Blood messenger RNA sequencing on 60 adults from the TREATgermany registry including 49 patients before and after dupilumab treatment, as well as from an independent cohort of 31 patients and 43 controls was performed. Patient clustering, differential expression, correlation and coexpression network analysis, and unsupervised learning were conducted.
RESULTS
AD patients showed pronounced inflammatory expression signatures with increased myeloid and IL-5-related patterns, and clearly segregated into 2 distinct clusters, with striking differences in particular for transcripts involved in eosinophil signaling. The eosinophil-high endotype showed a more pronounced global dysregulation, a positive correlation between disease activity and signatures related to IL-5 signaling, and strong correlations with several target proteins of antibodies or small molecules under development for AD. In contrast, the eosinophil-low endotype showed little transcriptomic dysregulation and no association between disease activity and gene expression. Clinical improvement with receipt of dupilumab was accompanied by a decrease of innate immune responses and an increase of lymphocyte signatures including B-cell activation and natural killer cell composition and/or function. The proportion of super responders was higher in the eosinophil-low endotype (32% vs 11%). Continued downregulation of IL18RAP, IFNG, and granzyme A in the eosinophil-high endotype suggests a residual disturbance of natural killer cell function despite clinical improvement.
CONCLUSION
AD can be stratified into eosinophilic and noneosinophilic endotypes; such stratification may be useful when assessing stratified trial designs and treatment strategies.
Topics: Adult; Dermatitis, Atopic; Gene Expression Profiling; Humans; Interleukin-5; Severity of Illness Index; Transcriptome
PubMed: 35182548
DOI: 10.1016/j.jaci.2022.02.001 -
Frontiers in Immunology 2020Tape-stripping is a minimally invasive approach for skin sampling that captures the cutaneous immune/barrier abnormalities in atopic dermatitis (AD). However,...
Tape-stripping is a minimally invasive approach for skin sampling that captures the cutaneous immune/barrier abnormalities in atopic dermatitis (AD). However, tape-strips have not been used to evaluate molecular changes with therapeutic targeting. In this study, we sought to characterize the proteomic signature of tape-strips from AD patients, before and after dupilumab therapy. Twenty-six AD patients were treated with every-other-week dupilumab 300 mg for 16 weeks. Tape-strips from lesional and non-lesional skin were collected before and after treatment, and analyzed with the Olink proteomic assay. Using criteria of fold-change>1.5 and FDR < 0.05, 136 proteins significantly decreased after dupilumab treatment, corresponding to an overall mean improvement of 66.2% in the lesional vs. non-lesional AD proteome. Significant decreases after dupilumab were observed in immune markers related to general inflammation (MMP12), Th2 (CCL13/CCL17), Th17/Th22 (IL-12B, CXCL1, S100A12), and innate immunity (IL-6, IL-8, IL-17C), while the Th1 chemokines CXCL9/CXCL10 remained elevated. Proteins related to atherosclerosis/cardiovascular risk (e.g., SELE/E-selectin, IGFBP7, CHIT1/ chitotriosidase-1, AXL) also significantly decreased after treatment. Dupilumab therapy suppressed AD-related immune biomarkers and atherosclerosis/cardiovascular risk proteins. Tape-strip proteomics may be useful for monitoring therapeutic response in real-life settings, clinical trials, and longitudinal studies for AD and beyond.
Topics: Adult; Antibodies, Monoclonal, Humanized; Biomarkers; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Male; Middle Aged; Proteins; Proteome; Proteomics; Signal Transduction; Skin; Time Factors; Treatment Outcome
PubMed: 32849633
DOI: 10.3389/fimmu.2020.01768 -
Acta Bio-medica : Atenei Parmensis Sep 2020Atopic dermatitis (AD) is a common inflammatory skin disease, clinically characterized by recurrent eczematous lesions and intense itching, leading to excoriations and...
Atopic dermatitis (AD) is a common inflammatory skin disease, clinically characterized by recurrent eczematous lesions and intense itching, leading to excoriations and susceptibility to cutaneous infections. Although it is considered a pediatric disorder, mainly starting in infancy, it is also very common in adults. Etiology of AD is complex and multifactorial: interaction between genetic susceptibility and environment, but also cutaneous barrier impairment, change in microbiome composition and innate and adaptive immune dysregulation are the main factors involved in the pathogenesis of the disease. Originally, the disorder was considered mediated by an imbalance towards a T-helper 2 response and excessive IgE production to allergens, but now it is recognized as a lifelong disposition with variable clinical expressivity, where dysfunctions of the epidermal barrier, immune system and microbiome play a central role. AD leads to a substantial psycho-social burden on patients and their relatives and increases the risk of other allergic and non allergic disorders. The real economic impact of AD is difficult to measure due to the broad spectrum of disease severity and the multiple direct and indirect costs, but the overall medical expenses seem to be very high and similar to those of other diseases such as diabetes. Currently, a multiple therapeutic approach is aimed only at improving the skin state, reducing itching and keeping a stable condition. New safety and curative treatments may be developed only after enhancing our understanding on the pathogenesis of AD and the heterogeneity of its clinical manifestations.
Topics: Adult; Allergens; Child; Dermatitis, Atopic; Humans; Immune System; Severity of Illness Index; Skin
PubMed: 33004781
DOI: 10.23750/abm.v91i11-S.10313 -
Acta Dermato-venereologica Feb 2023Clinical trials showed that upadacitinib, a selective Janus kinase-1 inhibitor, is effective for treatment of moderate-to-severe atopic dermatitis. However, daily...
Effectiveness of Upadacitinib in Patients with Atopic Dermatitis including those with Inadequate Response to Dupilumab and/or Baricitinib: Results from the BioDay Registry.
Clinical trials showed that upadacitinib, a selective Janus kinase-1 inhibitor, is effective for treatment of moderate-to-severe atopic dermatitis. However, daily practice studies are limited. This multicentre prospective study evaluated the effectiveness of 16 weeks of upadacitinib treatment for moderate-to-severe atopic dermatitis in adult patients, including those with previous inadequate response to dupilumab and/or baricitinib, in daily practice. A total of 47 patients from the Dutch BioDay registry treated with upadacitinib were included. Patients were evaluated at baseline, and after 4, 8 and 16 weeks of treatment. Effectiveness was assessed by clinician- and patient-reported outcome measurements. Safety was assessed by adverse events and laboratory assessments. Overall, the probabilities (95% confidence intervals) of achieving Eczema Area and Severity Index ≤ 7 and Numerical Rating Scale - pruritus ≤ 4 were 73.0% (53.7-86.3) and 69.4% (48.7-84.4), respectively. The effectiveness of upadacitinib was comparable in patients with inadequate response to dupilumab and/or baricitinib and in patients who were naïve for these treatments or who had stopped such treatments due to adverse events. Fourteen (29.8%) patients discontinued upadacitinib due to ineffectiveness, adverse events or both (8.5%, 14.9% and 6.4%, respectively). Most frequently reported adverse events were acneiform eruptions (n = 10, 21.3%), herpes simplex (n = 6, 12.8%), nausea and airway infections (both n = 4, 8.5%). In conclusion, upadacitinib is an effective treatment for patients with moderate-to-severe atopic dermatitis, including those with previous inadequate response to dupilumab and/or baricitinib treatment.
Topics: Adult; Humans; Dermatitis, Atopic; Prospective Studies; Double-Blind Method; Treatment Outcome; Severity of Illness Index
PubMed: 36794894
DOI: 10.2340/actadv.v103.5243 -
Biological Research Sep 2022Atopic dermatitis (AD) is highly comorbid with negative emotions such as anxiety and depression. Although acupuncture has demonstrated efficacy in AD, its influence on...
Atopic dermatitis (AD) is highly comorbid with negative emotions such as anxiety and depression. Although acupuncture has demonstrated efficacy in AD, its influence on comorbid anxiety and depression remains unclear. We sought to explore the impact and mechanisms of action of acupuncture on comorbid anxiety and depression of AD. AD-like skin lesions were induced by the topical application of MC903 to the mouse cheek. Acupuncture was performed at Gok-Ji (LI11) acupoints. AD-like phenotypes were quantified by lesion scores, scratching behavior, and histopathological changes. The effects of acupuncture on comorbid anxiety and depression-like behaviors were assessed using the elevated plus-maze (EPM), open-field tests (OFT), and tail-suspension test (TST). In addition, biochemical changes in the brain reward regions were investigated by immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine D1 receptor (D1R), phospho-dopamine and cAMP-regulated phosphoprotein-32 kDa (pDARPP-32), phospho-cAMP response element binding protein (pCREB), ΔFosB, and brain-derived neurotrophic factor (BDNF) in the nucleus accumbens, dorsolateral striatum, and ventral tegmental area. Acupuncture effectively improved the chronic itching and robust AD-like skin lesions with epidermal thickening. Additionally, it considerably reduced comorbid anxiety- and depression-like symptoms, as indicated by more time spent in the open arms of the EPM and in the center of the open field and less time spent immobile in the TST. Higher pCREB, ΔFosB, BDNF, and pDARPP-32 levels, and reduced TH and D1R protein expression in the brain reward regions of AD mice were reversed by acupuncture treatment. The beneficial effects of acupuncture on clinical symptoms (scratching behavior) and comorbid psychological distress in AD strongly correlated with dorsal striatal ΔFosB levels. Collectively, these data indicate that acupuncture had a significant, positive impact on comorbid anxiety- and depression-like behaviors by modulating neuroadaptation in the brain reward circuit in mice with AD, providing a novel perspective for the non-pharmacological management of psychiatric comorbidities of AD.
Topics: Acupuncture Therapy; Animals; Anxiety; Brain; Brain-Derived Neurotrophic Factor; Dermatitis, Atopic; Disease Models, Animal; Mice; Reward
PubMed: 36088447
DOI: 10.1186/s40659-022-00396-0