Treatment of atopic dermatitis: Recently approved drugs and advanced clinical development programs.

Atopic dermatitis (AD) represents the most common skin disease characterized by heterogeneous endophenotypes and a high disease burden. In Europe, six new systemic therapies for AD have been approved: the biologics dupilumab (anti-interleukin-4 receptor (IL-4R) α in 2017), tralokinumab (anti-IL-13 in 2021), lebrikizumab (anti-IL-13 in 2023), and the oral janus kinase (JAK) inhibitors (JAKi) targeting JAK1/2 (baricitinib in 2020 in the EU) or JAK1 (upadacitinib in 2021 and abrocitinib in 2022). Herein, we give an update on new approvals, long-term safety, and efficacy. Upadacitinib and abrocitinib have the highest short-term efficacy among the approved systemic therapies. In responders, dupilumab and tralokinumab catch up regarding long-term efficacy and incremental clinical benefit within continuous use. Recently, the European Medicines Agency has released recommendations for the use of JAKi in patients at risk (cardiovascular and thromboembolic diseases, malignancies, (former) smoking, and age ≥65 years). Furthermore, we give an overview on emerging therapies currently in Phase III trials. Among the topical therapies, tapinarof (aryl hydrocarbon receptor), ruxolitinib (JAK1/2i), delgocitinib (pan-JAKi), asivatrep (anti-transient receptor potential vanilloid), and phosphodiesterase-4-inhibitors (roflumilast, difamilast) are discussed. Among systemic therapies, current data on cord-blood-derived mesenchymal stem cells, CM310 (anti IL-4Rα), nemolizumab (anti-IL-31RA), anti-OX40/OX40L-antibodies, neurokinin-receptor-1-antagonists, and difelikefalin (κ-opioid-R) are reported.

Development of a clinical algorithm to predict phenotypic switches between atopic dermatitis and psoriasis (the "Flip-Flop" phenomenon).

BACKGROUND: Atopic dermatitis (AD) and psoriasis vulgaris (PV) are almost mutually exclusive diseases with different immune polarizations, mechanisms and therapeutic targets. Switches to the other disease ("Flip-Flop" [FF] phenomenon) can occur with or without systemic treatment and are often referred to as paradoxical reactions under biological therapy. METHODS: The objective was to develop a diagnostic algorithm by combining clinical criteria of AD and PV to identify FF patients. The algorithm was prospectively validated in patients enrolled in the CK-CARE registry in Bonn, Germany. Afterward, algorithm refinements were implemented based on machine learning. RESULTS: Three hundred adult Caucasian patients were included in the validation study (n = 238 with AD, n = 49 with PV, n = 13 with FF; mean age 41.2 years; n = 161 [53.7%] female). The total FF scores of the PV and AD groups differed significantly from the FF group in the validation data (p < .001). The predictive mean generalized Youden-Index of the initial model was 78.9% [95% confidence interval 72.0%-85.6%] and the accuracy was 89.7%. Disease group-specific sensitivity was 100% (FF), 95.0% (AD), and 61.2% (PV). The specificity was 89.2% (FF), 100% (AD), and 100% (PV), respectively. CONCLUSION: The FF algorithm represents the first validated tool to identify FF patients.

Chronic Prurigo.

Chronic prurigo (CPG) is a neuroinflammatory dermatosis characterized by prolonged pruritus lasting more than 6 weeks, pruriginous skin lesions, and repeated scratching. Patients with CPG suffer significantly from psychological distress and a marked impairment in their quality of life. The most common subtype of CPG is chronic nodular prurigo (CNPG, also called prurigo nodularis). In addition to the clinical features of CPG and the burden of disease, this CME article provides an overview of the significant advances in understanding the pathophysiology, including the associated therapeutic options for CPG. Dupilumab is the first approved therapy for moderate and severe CNPG to date from the European Medicines Agency (EMA) and the US Food & Drug Administration (FDA). It also highlights other agents currently being studied in Phase II and Phase III clinical, randomized, placebo-controlled trials. These include biologics such as nemolizumab (anti-IL-31-RA-mAb), vixarelimab/KPL-716 (anti-Oncostatin-M receptor ß-mAb), and barzolvolimab/CDX-0159 (anti-KIT-mAb), as well as Janus kinase inhibitors such as povorcitinib/INCB054707 and abrocitinib, and opioid modulators such as nalbuphine.

IL-13, periostin and dipeptidyl-peptidase-4 reveal endotype-phenotype associations in atopic dermatitis.

BACKGROUND: The heterogeneous (endo)phenotypes of atopic dermatitis (AD) require precision medicine. Currently, systemic therapy is recommended to patients with an Eczema Area and Severity Index (EASI)≥16. Previous studies have demonstrated an improved treatment response to the anti-interleukin (IL)-13 antibody tralokinumab in AD subgroups with elevated levels of the IL-13-related biomarkers dipeptidyl-peptidase (DPP)-4 and periostin. METHODS: Herein, 373 AD patients aged≥12 years were stratified by IL-13high , periostinhigh and DPP-4high endotypes using cross-sectional data from the ProRaD cohort Bonn. "High" was defined as >80th quantile of 47 non-atopic controls. We analyzed endotype-phenotype associations using machine-learning gradient boosting compared to logistic regression. RESULTS: AD severity and eosinophils correlated with IL-13 and periostin levels. Correlations of IL-13 with EASI were stronger in patients with increased (rs=0.482) than with normal (rs=0.342) periostin levels. We identified eosinophilia>6% and an EASI range of 5.5-17 dependent on the biomarker combination to be associated with increasing probabilities of biomarkerhigh endotypes. Also patients with mild-to-low-moderate severity (EASI<16) featured increased biomarkers (IL-13high : 41%, periostinhigh : 48.4%, DPP-4high : 22.3%). Herthoge sign (adjusted Odds Ratio (aOR)=1.89, 95% Confidence Interval (CI) [1.14-3.14]) and maternal allergic rhinitis (aOR=2.79-4.47) increased the probability of an IL-13high -endotype, "dirty neck" (aOR=2.83 [1.32-6.07]), orbital darkening (aOR=2.43 [1.08-5.50]), keratosis pilaris (aOR=2.21 [1.1-4.42]) and perleche (aOR=3.44 [1.72-6.86]) of a DPP-4high -endotype. CONCLUSIONS: A substantial proportion of patients with EASI<16 featured high biomarker levels suggesting systemic impact of skin inflammation already below the current cut-off for systemic therapy. Our findings facilitate the identification of patients with distinct endotypes potentially linked to response to IL-13-targeted therapy.

Atopic dermatitis: Correlation of distinct risk factors with age of onset in adulthood compared to childhood.

BACKGROUND: Atopic dermatitis (AD) has long been regarded as a primarily pediatric disease. However, there is growing evidence for a high rate of adult-onset AD. We aimed to characterize factors associated with adult-onset versus childhood-onset AD and controls. METHODS: We analyzed cross-sectional data of the CK-CARE-ProRaD cohorts Bonn, Augsburg, Davos, Zürich of 736 adult patients stratified by age of AD onset (childhood-onset <18 years: 76.4% (subsets: 0 to 2; ≥2 to 6; ≥7 to 11; ≥12 to 18); adult-onset ≥18 years: 23.6% (subsets: ≥18 to 40; ≥41 to 60; ≥61) and 167 controls (91 atopic, 76 non-atopic)). RESULTS: We identified active smoking to be associated with adult-onset AD versus controls (adjusted Odds Ratio (aOR) = 5.54 [95% Confidence Interval: 1.06-29.01] vs. controlsnon-atopic , aOR = 4.03 [1.20-13.45] vs. controlsatopic ). Conjunctivitis showed a negative association versus controlsatopic (aOR = 0.36 [0.14-0.91]). Food allergy (aOR = 2.93 [1.44-5.96]), maternal food allergy (aOR = 9.43 [1.10-80.95]), palmar hyperlinearity (aOR = 2.11 [1.05-4.25]), and academic background (aOR = 2.14 [1.00-4.54]) increased the odds of childhood-onset AD versus controlsatopic . Shared AD-associated factors were maternal AD (4-34x), increased IgE (2-20x), atopic stigmata (2-3x) with varying effect sizes depending on AD onset and control group. Patients with adult-compared to childhood-onset had doubled odds of allergic rhinitis (aOR = 2.15 [1.12-4.13]), but reduced odds to feature multiple (3-4) atopic comorbidities (aOR = 0.34 [0.14-0.84]). Adult-onset AD, particularly onset ≥61 years, grouped mainly in clusters with low contributions of personal and familial atopy and high frequencies of physical inactivity, childhood-onset AD, particularly infant-onset, mainly in "high-atopic"-clusters. CONCLUSIONS: The identified associated factors suggest partly varying endo- and exogeneous mechanisms underlying adult-onset versus childhood-onset AD. Our findings might contribute to better assessment of the individual risk to develop AD throughout life and encourage prevention by non-smoking and physical activity as modifiable lifestyle factors.

Gene expression patterns of Salpa thompsoni reveal remarkable differences in metabolism and reproduction near the Antarctic Polar Front.

Salpa thompsoni is an important grazer in the Southern Ocean and most abundant in the Antarctic Polar Front (APF) region. During recent decades, their distribution expanded southwards. However, it is unclear whether salps can maintain their populations in the high Antarctic regions throughout the year owing to a poor understanding of their physiological responses to changing environmental conditions. We examined gene expression signatures of salps collected in two geographically close regions south of the APF that differed in water mass composition and productivity. The observed differences in the expression of genes related to reproductive, cellular and metabolic processes reflect variations in water temperature and food supply between the two regions studied here. Our study contributes to a better understanding of the physiological responses of S. thompsoni to changing environmental conditions, and how the species may adapt to a changing environment through potential geographical population shifts under future climate change scenarios.

Cost-effectiveness and Quality of Specialized and Routine Care in a German Cohort of Patients with Chronic Pruritus.

Chronic pruritus is a prevalent interdisciplinary symptom with a strong influence on health-related quality of life. Patients need extensive diagnostics and long-term treatment. This retrospective and prospective cohort study compared routine and university-based specialized care in terms of cost-effectiveness and patient benefit. Direct medical and non-medical costs and patient-reported outcomes (PRO; pruritus intensity, quality of life, treatment needs and benefits) were assessed. Data analyses were conducted using descriptive methods and non-parametric statistical tests. A total of 300 adult patients (54.3% female) participated in the study. Six months after the treatment start in a specialized German pruritus care unit, the total costs were significantly reduced (mean total costs 686 € vs 433 € per patient per half year (total cohort); p < 0.001; mean out-of-pocket costs 198 € vs 124 € per half year (total cohort), p < 0.001). Pruritus intensity (numerical rating  scale 5.3 vs 3.7, p < 0.001), quality of life (Dermatology Life Quality Index 8.9 vs 5.7, p < 0.001) and patient benefit (Patient Benefit Index Pruritus 1.2 vs 2.1, p < 0.001) improved significantly (total  cohort). The results of this study show, that treatment of chronic pruritus patients in a specialized itch centre leads to an improvement in patient  benefit and reduces the economic burden at the same time.

Chronic Prurigo Including Prurigo Nodularis: New Insights and Treatments.

Chronic prurigo (CPG) is a neuroinflammatory, fibrotic dermatosis that is defined by the presence of chronic pruritus (itch lasting longer than 6 weeks), scratch-associated pruriginous skin lesions and history of repeated scratching. Patients with CPG experience a significant psychological burden and a notable impairment in their quality of life. Chronic prurigo of nodular type (CNPG; synonym: prurigo nodularis) represents the most common subtype of CPG. As CNPG is representative for all CPG subtypes, we refer in this review to both CNPG and CPG. We provide an overview of the clinical characteristics and assessment of CPG, the burden of disease and the underlying pathophysiology including associated therapeutic targets. The information provided results from a PubMed search for the latest publications and a database search for current clinical trials (ClinicalTrials.gov, EU Clinical Trials Register [European Medicines Agency]; using the following terms or combinations of terms: 'chronic prurigo', 'prurigo', 'prurigo nodularis', 'pathophysiology', 'therapy', 'biologics', 'treatment'). Dupilumab is the first authorized systemic therapy by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for CNPG to date. Topical and systemic agents that are currently under investigation in clinical randomized, placebo-controlled phase II and III trials such as biologics (e.g., nemolizumab, vixarelimab/KPL-716, barzolvolimab/CDX-0159), small molecules (ruxolitinib cream, povorcitinib/INCB054707, abrocitinib) and the opioid modulator nalbuphine are highlighted. In the last past 15 years, several milestones have been reached regarding the disease understanding of CPG such as first transcriptomic analysis, first terminology, first guideline, and first therapy approval in 2022, which contributed to improved medical care of affected patients. The broad range of identified targets, current case observations and initiated trials offers the possibility of more drug approvals in the near future.

Treatment-associated mRNA co-expression changes in monocytes of patients with posttraumatic stress disorder.

PTSD is a prevalent mental disorder that results from exposure to extreme and stressful life events and comes at high costs for both the individual and society. Therapeutic treatment presents the best way to deal with PTSD-the mechanisms underlying change after treatment, however, remain poorly understood. While stress and immune associated gene expression changes have been associated with PTSD development, studies investigating treatment effects at the molecular level so far tended to focus on DNA methylation. Here we use gene-network analysis on whole-transcriptome RNA-Seq data isolated from CD14+ monocytes of female PTSD patients (N = 51) to study pre-treatment signatures of therapy response and therapy-related changes at the level of gene expression. Patients who exhibited significant symptom improvement after therapy showed higher baseline expression in two modules involved in inflammatory processes (including notable examples IL1R2 and FKBP5) and blood coagulation. After therapy, expression of an inflammatory module was increased, and expression of a wound healing module was decreased. This supports findings reporting an association between PTSD and dysregulations of the inflammatory and the hemostatic system and mark both as potentially treatment sensitive.

The DNA methylation landscape of the human oxytocin receptor gene (OXTR): data-driven clusters and their relation to gene expression and childhood adversity.

The oxytocin receptor gene (OXTR) is of interest when investigating the effects of early adversity on DNA methylation. However, there is heterogeneity regarding the selection of the most promising CpG sites to target for analyses. The goal of this study was to determine functionally relevant clusters of CpG sites within the OXTR CpG island in 113 mother-infant dyads, with 58 of the mothers reporting childhood maltreatment (CM). OXTR DNA methylation was analyzed in peripheral/umbilical blood mononuclear cells. Different complexity reduction approaches were used to reduce the 188 CpG sites into clusters of co-methylated sites. Furthermore, associations between OXTR DNA methylation (cluster- and site-specific level) and OXTR gene expression and CM were investigated in mothers. Results showed that, first, CpG sections differed strongly regarding their statistical utility for research of individual differences in DNA methylation. Second, cluster analyses and Partial Least Squares (PLS) suggested two clusters consisting of intron1/exon2 and the protein-coding region of exon3, respectively, as most strongly associated with outcome measures. Third, cross-validated PLS regression explained 7% of variance in CM, with low cross-validated variance explained for the prediction of gene expression. Fourth, substantial mother-child correspondence was observed in correlation patterns within the identified clusters, but only modest correspondence outside these clusters. This study makes an important contribution to the mapping of the DNA methylation landscape of the OXTR CpG island by highlighting clusters of CpG sites that show desirable statistical properties and predictive value. We provide a Companion Web Application to facilitate the choice of CpG sites.

Therapeutic potential of biologics in prurigo nodularis.

INTRODUCTION: Prurigo nodularis (PN) or chronic prurigo of nodular type (CNPG) is a subtype of chronic prurigo with severe pruritus and neuroimmune underlying pathophysiology occurring in a plethora of dermatological, systemic, neurologic, and psychiatric conditions. AREAS COVERED: We review the increasing repertoire of biologics in the treatment of CNPG focusing on those targeting interleukins 4, 13, 31, oncostatin M and IgE. Presented information is based on a database research on current clinical trials (clinicaltrials.gov, European Clinical Trials Database (EudraCT), US clinical trial registry ICH-GCP) and a PubMed search for latest publications conducted with the combinations of the terms 'chronic prurigo,' 'prurigo nodularis,' 'pathophysiology,' 'treatment,' 'therapy', and 'biologics.' EXPERT OPINION: CNPG gets more and more attention as new therapeutic targets have been revealed in recent years, thus allowing the use of targeted approaches. The off-label advent of dupilumab offered advanced insight into the pathogenesis of CNPG and showed an impressive relief of pruritus in the vast majority of patients. New therapies including biologics (e.g. nemolizumab, tralokinumab, lebrikizumab), small molecules (e.g. neurokinin-1 receptor antagonists, janus kinase inhibitors) as well as mu-opioid receptor antagonists and nalbuphine, a µ-antagonist/κ-agonist, are in the pipeline and offer new hope for an improved future patient care.

[Pruritus in atopic dermatitis-comparative evaluation of novel treatment approaches]. / Pruritus bei atopischer Dermatitis ­ vergleichende Bewertung neuer Therapieansätze.

Chronic pruritus (duration ≥ 6 weeks) affects about 91% of patients suffering from atopic dermatitis (AD). Pruritus is often accompanied by sensations such as pain, burning, stinging, and heat, resulting in a high burden of affected patients; sleep and quality of life may be severely impaired. An important pillar of AD treatment is also to achieve sufficient control of pruritus. In addition to intensively used emollients, corticosteroids and calcineurin inhibitors have proven effective. In case of eczema affecting a large part of the body surface area (BSA), phototherapy may contribute to the healing of eczema and the relief of atopic pruritus. As to systemic therapies, several approved biologics (dupilumab, tralokinumab) and small molecules (baricitinib, upadacitinib, abrocitinib) lead to a rapid improvement of pruritus by interfering with the signal transduction of proinflammatory cytokines. While Janus kinase inhibitors initially lead to a faster relief of pruritus than biologics, the antipruritic efficacy of biologics and Janus kinase inhibitors seems to be similar in long-term use.

No long-term effects of antenatal synthetic glucocorticoid exposure on epigenetic regulation of stress-related genes.

Antenatal synthetic glucocorticoid (sGC) treatment is a potent modifier of the hypothalamic-pituitary-adrenal (HPA) axis. In this context, epigenetic modifications are discussed as potential regulators explaining how prenatal exposure to GCs might translate into persistent changes of HPA axis "functioning". The purpose of this study was to investigate whether DNA methylation and gene expression profiles of stress-associated genes (NR3C1; FKBP5; SLC6A4) may mediate the persistent effects of sGC on cortisol stress reactivity that have been previously observed. In addition, hair cortisol concentrations (hairC) were investigated as a valid biomarker of long-term HPA axis activity. This cross-sectional study comprised 108 term-born children and adolescents, including individuals with antenatal GC treatment and controls. From whole blood, DNA methylation was analyzed by targeted deep bisulfite sequencing. Relative mRNA expression was determined by RT-qPCR experiments and qBase analysis. Acute stress reactivity was assessed by the Trier Social Stress Test (TSST) measuring salivary cortisol by ELISA and hairC concentrations were determined from hair samples by liquid chromatography coupled with tandem mass spectrometry. First, no differences in DNA methylation and mRNA expression levels of the stress-associated genes between individuals treated with antenatal sGC compared to controls were found. Second, DNA methylation and mRNA expression levels were neither associated with cortisol stress reactivity nor with hairC. These findings do not corroborate the belief that DNA methylation and mRNA expression profiles of stress-associated genes (NR3C1; FKBP5; SLC6A4) play a key mediating role of the persistent effects of sGC on HPA axis functioning.

No evidence for intervention-associated DNA methylation changes in monocytes of patients with posttraumatic stress disorder.

DNA methylation patterns can be responsive to environmental influences. This observation has sparked interest in the potential for psychological interventions to influence epigenetic processes. Recent studies have observed correlations between DNA methylation changes and therapy outcome. However, most did not control for changes in cell composition. This study had two aims: first, we sought to replicate therapy-associated changes in DNA methylation of commonly assessed candidate genes in isolated monocytes from 60 female patients with post-traumatic stress disorder (PTSD). Our second, exploratory goal was to identify novel genomic regions with substantial pre-to-post intervention DNA methylation changes by performing whole-genome bisulfite sequencing (WGBS) in two patients with PTSD. Equivalence testing and Bayesian analyses provided evidence against physiologically meaningful intervention-associated DNA methylation changes in monocytes of PTSD patients in commonly investigated target genes (NR3C1, FKBP5, SLC6A4, OXTR). Furthermore, WGBS yielded only a limited set of candidate regions with suggestive evidence of differential DNA methylation pre- to post-therapy. These differential DNA methylation patterns did not prove replicable when investigated in the entire cohort. We conclude that there is no evidence for major, recurrent intervention-associated DNA methylation changes in the investigated genes in monocytes of patients with PTSD.

Comparison of soil organic carbon speciation using C NEXAFS and CPMAS 13C NMR spectroscopy.

We compared synchrotron-based C near-edge X-ray absorption fine structure (NEXAFS) and CPMAS 13C nuclear magnetic resonance (NMR) spectroscopy with respect to their precision and accuracy to quantify different organic carbon (OC) species in defined mixtures of soil organic matter source compounds. We also used both methods to quantify different OC species in organic surface horizons of a Histic Leptosol as well as in mineral topsoil and subsoil horizons of two soils with different parent material, stage of pedogenesis, and OC content (Cambisol: 15-30 OC mgg-1, Podzol: 0.9-7 OC mgg-1). CPMAS 13C NMR spectroscopy was more accurate and precise (mean recovery of different C functional groups 96-103%) than C NEXAFS spectroscopy (mean recovery 92-113%). For organic surface and topsoil samples, NMR spectroscopy consistently yielded larger O-alkyl C percentages and smaller alkyl C percentages than C NEXAFS spectroscopy. For the Cambisol subsoil samples both methods performed well and showed similar C speciation results. NEXAFS spectroscopy yielded excellent spectra with a high signal-to-noise ratio also for OC-poor Podzol subsoil samples, whereas this was not the case for CPMAS 13C NMR spectroscopy even after sample treatment with HF. Our results confirm the analytical power of CPMAS 13C NMR spectroscopy for a reliable quantitative OC speciation in soils with >10mgOCg-1. Moreover, they highlight the potential of synchrotron-based C NEXAFS spectroscopy as fast, non-invasive method to semi-quantify different C functional groups in soils with low C content (0.9-10mgg-1).