Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal.

Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8+ T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8+ T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy.

Effect of abrocitinib on skin biomarkers in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: This is the first report on the effects of abrocitinib, a Janus kinase 1-selective inhibitor, on the expression of skin biomarkers in patients with moderate-to-severe atopic dermatitis (AD). METHODS: JADE MOA (NCT03915496) was a double-blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]-12), epidermal hyperplasia (keratin-16 [KRT16]), T-helper 2 (Th2) immune response (C-C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks. RESULTS: A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP-12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose-dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26. CONCLUSIONS: Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate-to-severe AD.

Guselkumab demonstrates long-term efficacy and maintenance of treatment response postwithdrawal in systemic treatment-naïve patients and nonresponders to fumaric acid esters: results from parts II and III of a randomized active-comparator-controlled phase IIIb trial (POLARIS).

BACKGROUND: The anti-interleukin-23 antibody guselkumab (GUS) demonstrated favourable week 24 efficacy and safety over fumaric acid esters (FAE) in systemic treatment-naïve patients with moderate-to-severe plaque psoriasis (study part I). OBJECTIVES: To compare, in study part II, the sustainability of treatment responses (weeks 24-32) in GUS- and FAE-treated patients and treatment responses (weeks 32-56) in patients treated with GUS and FAE and in FAE nonresponders switching to GUS; and, in part III, to investigate the maintenance of response through week 100 in patients withdrawn from GUS at week 56. METHODS: At week 0, systemic treatment-naïve patients were randomized 1 : 1 to GUS or FAE as per label. At week 32, patients with a Psoriasis Area and Severity Index (PASI) 75 (≥ 75% improvement in PASI score) response (r) continued assigned treatment (GUSr-GUS; FAEr-FAE), whereas nonresponders (nr) received GUS (FAEnr-GUS; GUSnr-GUS). GUS-treated patients with a week 56 PASI 90 response (≥ 90% improvement in PASI score) were withdrawn (w) and followed until loss of response or week 100. RESULTS: At week 32, 98% (n = 54/55) of GUS- and 41% (n = 14/34) of FAE-treated patients were PASI 75 responders. At week 56, 91%, 50% and 80% of GUSr-GUS, FAEr-FAE and FAEnr-GUS patients, respectively, achieved a PASI 90 response; 72%, 29% and 45%, respectively, achieved a Dermatology Life Quality Index score of 0/1. At week 100, 44 weeks postwithdrawal, 47% (n = 17/36) and 25% (n = 3/12) of GUS-GUSw and FAE-GUSw patients, respectively, maintained a PASI score ≤ 5. Overall, the adverse event and discontinuation rates were lower for GUS than FAE. CONCLUSIONS: In these exploratory analyses, GUS, as a first-line systemic treatment or second-line systemic treatment in FAE nonresponders, was associated with long-term clinical efficacy up to week 100, including a withdrawal period.

Baricitinib treatment rapidly improves the four signs of atopic dermatitis assessed by Eczema Area and Severity Index (EASI) clinical subscores.

BACKGROUND: Baricitinib treatment in adults with moderate-to-severe atopic dermatitis (AD) has demonstrated rapid improvements in itch as well as AD sign severity and affected body surface area as assessed by the Eczema Area and Severity Index (EASI) total score, whether administered as monotherapy or in combination with topical corticosteroids (TCS). As EASI clinical signs differ in time course and associated antecedents, the effects of baricitinib on each individual clinical sign are of interest. OBJECTIVES: In this post hoc analysis, we aimed to investigate the effects of baricitinib on individual EASI subscores, namely excoriation, oedema/papulation, erythema and lichenification, in both monotherapy and TCS combination therapy trials. METHODS: We analysed the percent change from baseline in individual EASI subscores from three phase-III, double-blind, 16-week trials of baricitinib in monotherapy (BREEZE-AD1/BREEZE-AD2) and TCS combination therapy (BREEZE-AD7) cohorts via mixed model repeated measures (MMRM). RESULTS: Baricitinib 4 mg showed rapid and sustained improvements in all four clinical signs in both cohorts. Significant effects emerged at week 1 for excoriation, oedema/papulation and erythema scores in monotherapy (p < 0.001) and TCS combination therapy (p < 0.001, p < 0.01, p < 0.001), plateaued at week 4, and remained significant versus placebo through week 16. The effect on lichenification scores also emerged early, at week 1 in monotherapy (p < 0.05) and week 2 in combination therapy (p < 0.001), with scores continuously improving without a clear plateau. Effect magnitude was highest in excoriation scores, exhibiting near-maximal reduction in week 1 of monotherapy and remaining highest across all timepoints in combination therapy. CONCLUSIONS: Rapid and sustained improvements were observed across clinical signs of inflammation and particularly on excoriation following baricitinib treatment. Our findings suggest that selective inhibition of janus kinases 1 and 2 leads to rapid and sustained control of skin inflammation, and that rapid reductions in itch translate into early disruption of the itch-scratch cycle.

Real-world clinical, psychosocial and economic burden of atopic dermatitis: Results from a multicountry study.

BACKGROUND: Atopic dermatitis (AD), a relapsing, inflammatory skin disease, is associated with pruritus that can negatively affect patients' quality of life. Understanding the burden of AD is critical for informing and tailoring treatment and disease management to improve patient outcomes. This study characterized global treatment patterns and the clinical, psychosocial and economic burden of moderate-to-severe AD. METHODS: MEASURE-AD was a cross-sectional 28-country study in patients with physician-confirmed moderate-to-severe AD who were either receiving or eligible for systemic therapy for AD. Patients ≥12 years were enrolled between December 2019 and December 2020 while attending routine office or clinic visit. Primary outcomes included Worst Pruritus Numeric Rating Scale (WP-NRS; range: 0-10) and Dermatology Life Quality Index (DLQI; range: 0-30) and Children's DLQI (CDLQI; range: 0-30). Secondary outcomes included physician- and patient-reported clinical, psychosocial and economic burden. RESULTS: Of the 1591 patients enrolled, 1558 (1434 adults and 124 adolescents) fulfilled all patient selection criteria and were included in this analysis. Almost all patients (98.4%) in the total population were using AD medications and more than half (56%) were receiving systemic medication (15% systemic monotherapy). The most used systemic therapies were dupilumab (56.3%), systemic glucocorticoids (18.1%) and methotrexate (16.2%). Mean WP-NRS was 5.3 in the total population, and most patients (≥55%) reported moderate-to-severe pruritus (WP-NRS ≥4). Mean DLQI was 10.8 and mean CDLQI was 9.6. Secondary endpoints demonstrated substantial clinical, psychosocial, and economic burden of disease. Subgroup analysis demonstrated that patients receiving systemic therapy had lower disease burden than those not taking systemic medications. CONCLUSIONS: While systemic therapy lowers overall disease burden, patients with moderate-to-severe AD continue to have substantial multidimensional disease burden and uncontrolled disease. Overall, there is a need for effective disease management, including effective treatments that improve patients' psychosocial outcomes and reduce the economic burden of AD.

The neglected twin: Nummular eczema is a variant of atopic dermatitis with codominant TH2/TH17 immune response.

BACKGROUND: Nummular eczema (NE) is a common chronic inflammatory skin disease characterized by multiple, pruritic, discoid-shaped lesions. Since the underlying immune mechanisms are not fully understood, it is unclear whether NE should be regarded as variant of atopic dermatitis (AD) or a distinct disease. OBJECTIVE: We compared the clinical, histopathologic, and molecular signatures of NE with that of type 2 and type 3 skin diseases. METHODS: We performed bulk RNA sequencing as well as histologic and clinical studies in lesional and nonlesional skin biopsy specimens from NE (n = 50), AD (n = 47), and psoriasis (n = 90) patients. RESULTS: NE displayed typical hallmarks of AD, such as an impaired epidermal barrier, microbial colonization, spongiosis, and eosinophil infiltration, but also aspects of psoriasis, including increased epidermal thickness, number of Ki-67+ cells, and neutrophilic infiltration. At the gene expression level, neutrophil-attracting cytokines (IL19, CXCL8, CXCL5) were upregulated, whereas TH2-related cytokines (IL13, CCL17, CCL18, CCL26, CCL27) were similarly expressed in NE compared to AD. Principal component analysis of transcriptome data from lesional skin showed that AD and NE cluster together distinct of psoriasis. In line with this, an established molecular classifier identified NE as AD rather than psoriasis. Finally, we demonstrated clinical and molecular efficacy of dupilumab treatment in NE. CONCLUSION: NE shows overlapping type 2 and type 3 immune signatures, while type 2 immunity predominates and should be the primary target of specific therapeutic interventions. This supports the view of NE as a variant of AD.

Characterization of High and Low IFNG-Expressing Subgroups in Atopic Dermatitis.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, with an increasing number of targeted therapies available. While biologics to treat AD exclusively target the key cytokines of type 2 immunity, Janus kinase inhibitors target a broad variety of cytokines, including IFN-γ. To better stratify patients for optimal treatment outcomes, the identification and characterization of subgroups, especially with regard to their IFNG expression, is of great relevance, as the role of IFNG in AD has not yet been fully clarified. This study aims to define AD subgroups based on their lesional IFNG expression and to characterize them based on their gene expression, T cell secretome and clinical attributes. RNA from the lesional and non-lesional biopsies of 48 AD patients was analyzed by RNA sequencing. Based on IFNG gene expression and the release of IFN-γ by lesional T cells, this cohort was categorized into three IFNG groups (high, medium, and low) using unsupervised clustering. The low IFNG group showed features of extrinsic AD with a higher prevalence of atopic comorbidities and impaired epidermal lipid synthesis. In contrast, patients in the high IFNG group had a higher average age and an activation of additional pro-inflammatory pathways. On the cellular level, higher amounts of M1 macrophages and natural killer cell signaling were detected in the high IFNG group compared to the low IFNG group by a deconvolution algorithm. However, both groups shared a common dupilumab response gene signature, indicating that type 2 immunity is the dominant immune shift in both subgroups. In summary, high and low IFNG subgroups correspond to intrinsic and extrinsic AD classifications and might be considered in the future for evaluating therapeutic efficacy or non-responders.

Dermatologic adverse events caused by biologic treatments - Pathogenesis and management.

Biologics are approved for various dermatologic, allergic, rheumatic, and gastroenterologic inflammatory diseases, as well as for numerous malignancies. The dermatologic adverse events from treatment with biologics may resemble primary inflammatory diseases but differ in pathogenesis. In this article, we describe five different pathogenic mechanisms of dermatologic adverse events. By studying these mechanisms, we hope to gain valuable insights into the pathogenesis of primary inflammatory diseases. In addition, in this article, we provide recommendations for the treatment and management of the dermatological adverse events induced by biologics.

Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: a randomised, double-blind, multicentre phase 3 trial.

BACKGROUND: Phase 3 trials have assessed efficacy of abrocitinib versus placebo in moderate-to-severe atopic dermatitis, a common immunoinflammatory skin disease. This study assessed the efficacy and safety of abrocitinib versus dupilumab. METHODS: This randomised, double-blind, double-dummy, active-controlled, parallel-treatment, phase 3 trial enrolled adults with moderate-to-severe atopic dermatitis who requir=ed systemic therapy or had inadequate response to topical medications. Participants were enrolled from 151 sites, located in Australia, Bulgaria, Canada, Chile, Finland, Germany, Hungary, Italy, Latvia, Poland, Slovakia, South Korea, Spain, Taiwan, and the USA. These participants were then randomly assigned (1:1) with block randomisation to receive oral abrocitinib (200 mg per day) or subcutaneous dupilumab (300 mg every 2 weeks) for 26 weeks. Participants were required to apply topical corticosteroids (medium or low potency), topical calcineurin inhibitors, or a topical phosphodiesterase 4 inhibitor to active lesion areas. Primary endpoints were response based on achieving a 4 point or higher improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) at week 2 and a 90% or better improvement in Eczema Area and Severity Index (EASI-90) at week 4. Family-wise type 1 error was controlled via a sequential multiple-testing procedure (two sided, α=0·05). Randomly assigned participants who received at least one dose of study intervention were included in the efficacy and safety analysis sets. This trial was completed on July 13, 2021 (NCT04345367). FINDINGS: Between June 11, 2020, and Dec 16, 2020, 940 patients were screened and 727 were enrolled (362 in the abrocitinib group and 365 in the dupilumab group). Compared with dupilumab, a larger proportion of patients treated with abrocitinib reached the primary outcomes, PP-NRS4 at week 2 (172 [48%] of 357, 95% CI 43·0-53·4 vs 93 [26%] of 364, 21·1-30·0; difference 22·6%, 15·8-29·5; p<0·0001), and EASI-90 at week 4 (101 [29%] of 354, 23·8-33·2 vs 53 [15%] of 364, 10·9-18·2; difference 14·1%, 8·2-20·0; p<0·0001). Treatment-emergent adverse events were reported by 268 (74%) of 362 patients treated with abrocitinib and by 239 (65%) of 365 patients treated with dupilumab. Two non-treatment-related deaths occurred in the abrocitinib group. INTERPRETATION: Abrocitinib 200 mg per day was more efficacious than dupilumab in adults with moderate-to-severe atopic dermatitis on background topical therapy in inducing early reductions of itch and atopic dermatitis disease signs. Both treatments were well tolerated over 26 weeks. FUNDING: Pfizer.

Matrix metalloproteinases in coronary artery disease and myocardial infarction.

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Most cardiovascular deaths are caused by ischaemic heart diseases such as myocardial infarction (MI). Hereby atherosclerosis in the coronary arteries often precedes disease manifestation. Since tissue remodelling plays an important role in the development and progression of atherosclerosis as well as in outcome after MI, regulation of matrix metalloproteinases (MMPs) as the major ECM-degrading enzymes with diverse other functions is crucial. Here, we provide an overview of the expression profiles of MMPs in coronary artery and left ventricular tissue using publicly available data from whole tissue to single-cell resolution. To approach an association between MMP expression and the development and outcome of CVDs, we further review studies investigating polymorphisms in MMP genes since polymorphisms are known to have an impact on gene expression. This review therefore aims to shed light on the role of MMPs in atherosclerosis and MI by summarizing current knowledge from publically available datasets, human studies, and analyses of polymorphisms up to preclinical and clinical trials of pharmacological MMP inhibition.

Biomarkers associated with the development of comorbidities in patients with atopic dermatitis: A systematic review.

Biomarkers associated with the development of comorbidities in atopic dermatitis (AD) patients have been reported, but have not yet been systematically reviewed. Seven electronic databases were searched, from database inception to September 2021. English language randomized controlled trials, prospective and retrospective cohort, and case-control studies that investigated the association between a biomarker and the development of comorbidities in AD patients were included. Two authors independently screened the records for eligibility, one extracted all data, and critically appraised the quality of studies and risk of bias. Fifty six articles met the inclusion criteria, evaluating 146 candidate biomarkers. The most frequently reported biomarkers were filaggrin mutations and allergen specific-IgE. Promising biomarkers include specific-IgE and/or skin prick tests predicting the development of asthma, and genetic polymorphisms predicting the occurrence of eczema herpeticum. The identified studies and biomarkers were highly heterogeneous, and associated with predominately moderate-to-high risk of bias across multiple domains. Overall, findings were inconsistent. High-quality studies assessing biomarkers associated with the development of comorbidities in people with AD are lacking. Harmonized datasets and independent validation studies are urgently needed.

The integration of large-scale public data and network analysis uncovers molecular characteristics of psoriasis.

In recent years, a growing interest in the characterization of the molecular basis of psoriasis has been observed. However, despite the availability of a large amount of molecular data, many pathogenic mechanisms of psoriasis are still poorly understood. In this study, we performed an integrated analysis of 23 public transcriptomic datasets encompassing both lesional and uninvolved skin samples from psoriasis patients. We defined comprehensive gene co-expression network models of psoriatic lesions and uninvolved skin. Moreover, we curated and exploited a wide range of functional information from multiple public sources in order to systematically annotate the inferred networks. The integrated analysis of transcriptomics data and co-expression networks highlighted genes that are frequently dysregulated and show aberrant patterns of connectivity in the psoriatic lesion compared with the unaffected skin. Our approach allowed us to also identify plausible, previously unknown, actors in the expression of the psoriasis phenotype. Finally, we characterized communities of co-expressed genes associated with relevant molecular functions and expression signatures of specific immune cell types associated with the psoriasis lesion. Overall, integrating experimental driven results with curated functional information from public repositories represents an efficient approach to empower knowledge generation about psoriasis and may be applicable to other complex diseases.

Autosomal dominant inheritance with sex-limited manifestation: An unusual mode of transmission in humans and animals.

Autosomal dominant, sex-limited inheritance is a distinct mode of transmission that should not be conflated with X-linked inheritance. From animal studies, we know that sex-limited inheritance implies the chance to "turn off" some genes in either males or females, in order to meliorate the phenotype, for example, by improving the fecundity. In this way, sex-limited genes play an important role in the evolution of diverse species of animals. In human genetics, however, the biological significance of sex-limited genes is unknown until today. When screening the literature, we found, thus far, three human examples of sex-limited transmission. Autosomal dominant, male-limited inheritance has meticulously been studied in a particular form of precocious puberty. Limitation to females was described in autosomal dominant lymphedema of the CESLR1 type, being underpinned by convincing molecular findings. Another example is white lentiginosis of Grosshans that shows clinical evidence of such mode of transmission although molecular findings are lacking as yet. In the animal kingdom, autosomal dominant sex-limited inheritance is a well-established phenomenon that has extensively been studied in various species such as butterflies, damselflies, fish (cichlids), and birds. Hence, at this point in time, it seems likely that other human examples of this mode of inheritance have previously been reported or will be published in the future.

Bimekizumab efficacy and safety in patients with moderate to severe plaque psoriasis: Two-year interim results from the open-label extension of the randomized BE RADIANT phase 3b trial.

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that inhibits interleukin-17A/F. Bimekizumab is more efficacious than secukinumab over 1 year in the treatment of psoriasis. OBJECTIVE: Evaluate the safety and efficacy of bimekizumab through 2 years in patients with moderate to severe plaque psoriasis. METHODS: The BE RADIANT phase 3b randomized controlled trial consisted of a 48-week double-blinded period, where patients received bimekizumab (320 mg every 4 or 8 weeks) or secukinumab (300 mg weekly to Week 4, then every 4 weeks), and an open-label extension (OLE). From Week 48, all patients received bimekizumab in the OLE. RESULTS: At Week 48, more patients achieved complete skin clearance (PASI 100; modified non-responder imputation) with bimekizumab than secukinumab (74.8% vs 52.8%). PASI 100 responses were maintained to Week 96 in continuous bimekizumab patients (70.8%); patients who switched from secukinumab to bimekizumab had increased rates at Week 96 (76.6%). The most common adverse events were: nasopharyngitis, oral candidiasis, and urinary tract infection. Safety data were consistent with the known safety profile of bimekizumab. LIMITATIONS: Limited racial diversity; overlap with the COVID-19 pandemic. CONCLUSIONS: High PASI 100 responses achieved with bimekizumab over 48 weeks were sustained through Week 96; secukinumab patients who switched to bimekizumab achieved similar responses by Week 96.

Efficacy and safety of switching from dupilumab to upadacitinib versus continuous upadacitinib in moderate-to-severe atopic dermatitis: Results from an open-label extension of the phase 3, randomized, controlled trial (Heads Up).

BACKGROUND: Characterization of upadacitinib use and switching from dupilumab to upadacitinib among patients with moderate-to-severe atopic dermatitis (AD) is needed. OBJECTIVE: To evaluate the long-term safety and efficacy of continuous upadacitinib 30 mg and switching to upadacitinib after 24 weeks of dupilumab. METHODS: Adults who completed the phase 3b clinical trial of oral upadacitinib 30 mg vs injectable dupilumab 300 mg (Heads Up) and entered a 52-week open-label extension (OLE) (NCT04195698) were included. All patients received 30-mg upadacitinib during the open-label period. We report results of a prespecified interim OLE 16-week analysis. RESULTS: Patients (n = 239) continuing upadacitinib maintained high levels of skin and itch response. Patients (n = 245) switching from dupilumab experienced additional incremental improvements in clinical responses within 4 weeks of starting upadacitinib. Most patients who did not achieve adequate clinical responses with dupilumab did so with upadacitinib. The safety profile of upadacitinib up to 40 weeks (week 16 of OLE) was consistent with previous phase 3 AD studies, with no new safety risks observed. LIMITATIONS: Open-label study design. CONCLUSIONS: Clinical responses are maintained with continuous upadacitinib through 40 weeks and patients regardless of prior dupilumab response experienced improved outcomes when switched to upadacitinib. No new safety risks were observed.

Histology-based classifier to distinguish early mycosis fungoides from atopic dermatitis.

BACKGROUND: Histopathological differentiation of early mycosis fungoides (MF) from benign chronic inflammatory dermatoses remains difficult and often impossible, despite the inclusion of all available diagnostic parameters. OBJECTIVE: To identify the most impactful histological criteria for a predictive diagnostic model to discriminate MF from atopic dermatitis (AD). METHODS: In this multicentre study, two cohorts of patients with either unequivocal AD or MF were evaluated by two independent dermatopathologists. Based on 32 histological attributes, a hypothesis-free prediction model was developed and validated on an independent patient's cohort. RESULTS: A reduced set of two histological features (presence of atypical lymphocytes in either epidermis or dermis) was trained. In an independent validation cohort, this model showed high predictive power (95% sensitivity and 100% specificity) to differentiate MF from AD and robustness against inter-individual investigator differences. LIMITATIONS: The study investigated a limited number of cases and the classifier is based on subjectively evaluated histological criteria. CONCLUSION: Aiming at distinguishing early MF from AD, the proposed binary classifier performed well in an independent cohort and across observers. Combining this histological classifier with immunohistochemical and/or molecular techniques (such as clonality analysis or molecular classifiers) could further promote differentiation of early MF and AD.

Eczematized psoriasis - a frequent but often neglected variant of plaque psoriasis.

Psoriasis is a common chronic inflammatory skin disease that causes systemic inflammation and severely impacts the patient's quality of life. Several highly effective therapeutics for psoriasis have been approved in recent years. However, in real life, a high proportion of patients either do not experience the clinical improvement observed in clinical trials or develop a secondary loss of efficacy. This may be a result of unrecognized endotypes of psoriasis that need to be characterized in greater depth to enable selection of an appropriate therapy. Eczematized psoriasis, which occurs in approximately 5-10% of patients with psoriasis, is an often-neglected variant of psoriasis. The term "eczematized psoriasis" refers to patients developing psoriasis with similarities to eczema. These patients typically present with severe itching, and skin biopsies often reveal eosinophil granulocytes, serum crusts, or spongiosis, which are frequently observed in eczema. From an immunological perspective, additional signaling pathways that are responsible for eczema reactions might be activated in eczematized psoriasis compared to classical plaque psoriasis. This review summarizes the key clinical, histological, and immunological features of eczematized psoriasis, proposes diagnostic criteria, and evaluates the therapeutic options for eczematized psoriasis.

Status quo and future perspectives of molecular diagnostics in dermatology.

Molecular diagnostics (MDx) has become an indispensable pillar of diagnostics in dermatology. Modern sequencing technologies allow for identification of rare genodermatoses, analysis of somatic mutations in melanoma are prerequisite for targeted therapies, and cutaneous infectious pathogens are quickly detected by PCR and other amplification methods. However, to push innovation in molecular diagnostics and tackle so far unmet clinical needs, research activities need to be bundled and the pipeline from idea to MDx product clearly rolled out. Only then, the requirements for technical validity and clinical utility of novel biomarkers can be fulfilled and the long-term vision of personalized medicine will be realized.

EAACI Biologicals Guidelines-Omalizumab for the treatment of chronic spontaneous urticaria in adults and in the paediatric population 12-17 years old.

Chronic spontaneous urticaria (CSU) imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity and insufficient efficacy of classical drugs such as H1 R-antihistamines. Better understanding of the mechanisms has enabled a stratified approach to the management of CSU, supporting the use of targeted treatment with omalizumab. However, many practical issues including selection of responders, the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based) and its cost-effectiveness still require further clarification. The EAACI Guidelines on the use of omalizumab in CSU follow the GRADE approach in formulating recommendations for each outcome. In addition, future therapeutic approaches and perspectives as well as research priorities are discussed.

Efficacy and safety of baricitinib in combination with topical corticosteroids in patients with moderate-to-severe atopic dermatitis with inadequate response, intolerance or contraindication to ciclosporin: results from a randomized, placebo-controlled, phase III clinical trial (BREEZE-AD4).

BACKGROUND: Baricitinib, an oral selective Janus kinase (JAK)1 and JAK 2 inhibitor, was shown to improve the signs and symptoms of moderate-to-severe atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of baricitinib with background topical corticosteroids (TCS) in patients with moderate-to-severe AD and inadequate response, intolerance or contraindication to ciclosporin A (CA). METHODS: In this double-blind, randomized, placebo-controlled, phase III study, patients were randomized 1: 1: 2: 1 to placebo (N = 93), baricitinib 1 mg (N = 93), 2 mg (N = 185) or 4 mg (N = 92) with background TCS. The primary endpoint was the proportion of patients receiving baricitinib 4 mg or 2 mg (+ TCS) vs. placebo + TCS who achieved ≥ 75% improvement from baseline in the Eczema Area and Severity Index (EASI 75) at week 16. RESULTS: Baricitinib 4 mg + TCS was superior to placebo + TCS for EASI 75 (4 mg: 32%, placebo: 17%, P = 0·031) at week 16 and for improvements in itch, skin pain and number of night-time awakenings owing to itch. Improvements were maintained through 52 weeks of treatment. Treatment-emergent adverse events (TEAEs) were more common with baricitinib than placebo (+ TCS); most were mild or moderate. The most frequent TEAEs with baricitinib 4 mg + TCS were nasopharyngitis, herpes simplex, influenza and headache. No deaths or deep vein thromboses were reported. CONCLUSIONS: Baricitinib 4 mg + TCS improved the signs and symptoms of moderate-to-severe AD through 52 weeks of treatment in patients with inadequate response, intolerance or contraindication to CA. The safety profile was consistent with previous studies of baricitinib in moderate-to-severe AD. What is already known about this topic? Ciclosporin A is indicated for the treatment of atopic dermatitis that is refractory to topical therapies. However, its use is limited by safety concerns and it may not provide adequate response for some patients. Baricitinib, an oral selective Janus kinase (JAK)1 and JAK2 inhibitor, has been shown to improve the signs and symptoms of moderate-to-severe atopic dermatitis as a monotherapy or in combination with topical corticosteroids. What does this study add? Baricitinib combined with background low- or moderate-potency topical corticosteroids provided improvements in the signs and symptoms of moderate-to-severe atopic dermatitis through 1 year of treatment in patients with a contraindication, intolerance or failure to respond to ciclosporin A. The most common treatment-emergent adverse events with baricitinib 4 mg were nasopharyngitis, herpes simplex, influenza and headache. The safety profile was consistent with previous studies in patients with moderate-to-severe atopic dermatitis.