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Atopic dermatitis (AD) is a common, chronic inflammatory skin disorder driven by an intricate interplay of genetic, environmental, and immunological factors. As a clinically heterogenous condition, AD may be stratified into subtypes based on factors including, chronicity, immunoglobulin E levels, severity, age, and ethnicity. Transcriptomic and proteomic analyses in skin and blood help elucidate the underlying molecular mechanisms of these AD subtypes, referred to as AD endotypes. Further characterizing AD endotypes using reliable biomarkers can facilitate the development of more effective and personalized therapeutics and improve our tools for monitoring disease progression and therapeutic response across a diverse subset of patients. Here, we aim to provide perspective on the latest research regarding AD stratification using skin and blood-based studies and insight into the implications of these findings on the future of AD research and clinical practice. The precise stratification of AD endotypes will allow for the development of reliable biomarkers and a more personalized medical treatment approach. Clinical practice and trials will eventually be able to bridge clinical with molecular data to optimize individualized treatments and more effectively monitor treatment response. [ABSTRACT FROM AUTHOR]

Background Secukinumab, an anti-interleukin (IL)-17A monoclonal antibody, induces histological and molecular resolution of psoriatic plaques by 12 weeks. However, the long-term effects of secukinumab on the molecular resolution of psoriatic inflammation remain unknown. Objectives To investigate the molecular resolution of psoriasis following 52 weeks of secukinumab treatment. Methods This was a two-part phase II randomized double-blinded placebo-controlled 52-week study of patients with moderate-to-severe psoriasis receiving secukinumab 300 mg (NCT01537432). Psoriatic lesional and nonlesional skin biopsies were obtained at baseline and at weeks 12 and 52, and the composition of the residual disease genomic profile (RDGP; i.e. 'molecular scar') of biopsies from secukinumab responders analysed. Results After 52 weeks of treatment, 14 of 24 enrolled patients were considered to be clinical responders [≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75)], 4 of 24 were considered to be nonresponders (< PASI 75) and 6 of 24 patients were lost to follow-up; both the histological and transcriptomic profiles of PASI 75 responders improved from week 12 to week 52. RDGP transcripts of histological responders only partially overlapped between weeks 12 and 52, despite a similar number of transcripts in each RDGP; specifically, four novel transcript subsets showed distinct expression dynamics between weeks 12 and 52 ('slow-resolving', 'recurring', 'persistent' and 'resolved'), with anti-inflammatory and immunomodulatory genes (e.g. SOCS1 , CD207 and IL37) notably restored at week 52. Shorter disease duration prior to secukinumab treatment coincided with greater transcript improvements at weeks 12 and 52. Conclusions Secukinumab improves the histological and molecular phenotype of psoriatic lesional skin up to 52 weeks of treatment; these results suggest possible mechanisms that drive long-term control of psoriasis. [ABSTRACT FROM AUTHOR]

Background Secukinumab is effective against a range of psoriatic manifestations. Investigating psoriasis (PsO) relapse following secukinumab discontinuation could provide insights into long-term PsO remission. Objectives To examine PsO relapse rates on treatment discontinuation following 1 year of secukinumab treatment. Methods This study (clinical trial number: NCT01544595) is an extension of the phase III ERASURE/FIXTURE studies in patients with moderate-to-severe plaque PsO. After 1 year of secukinumab 300 mg or 150 mg treatment, participants who had responded to treatment with a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) at week 52 were randomly assigned to receive placebo (n = 120 and n = 100, respectively). On relapse, patients receiving placebo were switched to their previous secukinumab dose. The study primary outcome was the nonrelapse rate after secukinumab withdrawal. Results Following the last dose of secukinumab 300 mg, 20.8% (25/120) and 10.0% (12/120) of patients who switched to placebo did not relapse at 1 and 2 years after discontinuation, respectively. Patients who received secukinumab 150 mg for 1 year showed a lower proportion of nonrelapse following treatment discontinuation [14% (14/100) and 6% (6/100)] at 1 and 2 years, respectively. Patients who did not relapse maintained low mean PASI (2.8) at 1 year drug free vs. baseline (20.9); 1.7 at 2 years drug free vs. baseline (19.2), following an initial 52-week treatment with secukinumab 300 mg. Disease duration (P = 0.02) and severity (P = 0.02) were significantly associated with time to relapse in patients initially treated with secukinumab 300 mg; patients with shorter disease duration and lower baseline PASI remained relapse-free for longer. Conclusions Following discontinuation of secukinumab, a proportion of patients stayed relapse-free. Further, patients with shorter disease duration remained relapse-free for longer, suggesting that earlier treatment with secukinumab may result in long-term clinical control of moderate-to-severe PsO. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking. Previous reports raise a potential role for eosinophils in HS, showing a strong association of eosinophil levels with disease severity. To investigate eosinophils in HS, we recruited patients and matched healthy controls and then performed flow‐cytometry studies, eosinophil stimulation assays, and lesional skin staining for eosinophils. We found that HS patients reported similar levels of pain and itch. Compared to matched controls, HS blood exhibited decreased mature eosinophils and increased numbers of immature eosinophils, coupled with a significant increase in dermal eosinophilic infiltrates. Additionally, IL‐17RA+ eosinophils were highly and significantly correlated with multiple HS‐related clinical scores. In both stimulated and unstimulated conditions, HS eosinophils showed an inflammatory phenotype versus controls, including an increase in costimulatory T‐ and B‐cell markers (e.g. CD5 and CD40) following all stimulations (TNFα/IL‐17A/IL‐17F). These findings highlight the significance of pruritus in HS and suggest a higher turnover of eosinophils in HS blood, potentially due to the consumption of eosinophils in skin lesions. Our data delineate the features and functions of eosinophils in HS and suggest that eosinophils participate in disease pathogenesis, advancing Th17‐related inflammation. Further studies are needed to investigate eosinophils' response to current HS treatments and their potential as a therapeutic target in the disease. [ABSTRACT FROM AUTHOR]

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic disabling and debilitating inflammatory disease with a high unmet medical need. The prevalence of HS reported in most studies is 1–2%, although it is likely to be under-reported and estimates vary globally owing to variance in data collection methods, ethnicity, geographical location and under-diagnosis. HS is characterized by persistent, painful cutaneous nodules, abscesses and draining tunnels commonly affecting the axillary, anogenital, inguinal and perianal/gluteal areas. Over time, chronic uncontrolled inflammation results in irreversible tissue destruction and scarring. Although the pathophysiology of HS has not been fully elucidated, the tumour necrosis factor (TNF)-α and interleukin (IL)-17 pathways have an important role, involving multiple cytokines. Currently, treatment options include topical medications; systemic therapies, including repeated and/or rotational courses of systemic antibiotics, retinoids and hormonal therapies; and various surgical procedures. The anti-TNF-α antibody adalimumab is currently the only biologic approved by both the US Food and Drug Administration and the European Medicines Agency for HS; however, its efficacy varies, with a clinical response reported in approximately 50% of patients in phase III trials. HS is a rapidly evolving field of discovery, with a diverse range of agents with distinct mechanisms of action currently being explored in clinical trials. Several other promising therapeutic targets have recently emerged, and agents targeting the IL-17 and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways are the most advanced in ongoing or completed phase III clinical trials. Alongside limited therapeutic options, significant challenges remain in terms of diagnosis and disease management, with a need for better treatment outcomes. Other unmet needs include significant diagnostic delays, thus missing the therapeutic 'window of opportunity'; the lack of standardized outcome measures in clinical trials; and the lack of established, well-defined disease phenotypes and biomarkers. [ABSTRACT FROM AUTHOR]

Melanoma accounts for the majority of skin cancer‐related mortality, highlighting the need to better understand melanoma initiation and progression. In‐depth molecular analysis of neoplastic melanocytes in whole tissue biopsies may be diluted by inflammatory infiltration, which may obscure gene signatures specific to neoplastic cells. Thus, a method is needed to precisely uncover molecular changes specific to tumor cells from a limited sample of primary melanomas. Here, we performed laser capture microdissection (LCM) and gene expression profiling of patient‐derived frozen sections of pigmented lesions and primary cutaneous melanoma. Compared to bulk tissue analysis, analysis of LCM‐derived samples identified 9528 additional differentially expressed genes (DEGs) including melanocyte‐specific genes like PMEL and TYR, with enriched of pathways related to cell proliferation. LCM methodology also identified potentially targetable kinases specific to melanoma cells that were not detected by bulk tissue analysis. Taken together, our data demonstrate that there are marked differences in gene expression profiles depending on the method of sample isolation. We found that LCM captured higher expression of melanoma‐related genes while whole tissue biopsy identified a wider range of inflammatory markers. Taken together, our data demonstrate that LCM is a valid approach to identify melanoma‐specific changes using a relatively small amount of primary patient‐derived melanoma sample. [ABSTRACT FROM AUTHOR]

Background: Our knowledge of etiopathogenesis of atopic dermatitis (AD) is largely derived from skin biopsies, which are associated with pain, scarring and infection. In contrast, tape‐stripping is a minimally invasive, nonscarring technique to collect skin samples. Methods: To construct a global AD skin transcriptomic profile comparing tape‐strips to whole‐skin biopsies, we performed RNA‐seq on tape‐strips and biopsies taken from the lesional skin of 20 moderate‐to‐severe AD patients and the skin of 20 controls. Differentially expressed genes (DEGs) were defined by fold‐change (FCH) ≥2.0 and false discovery rate <0.05. Results: We detected 4104 (2513 Up; 1591 Down) and 1273 (546 Up; 727 Down) DEGs in AD versus controls, in tape‐strips and biopsies, respectively. Although both techniques captured dysregulation of key immune genes, tape‐strips showed higher FCHs for innate immunity (IL‐1B, IL‐8), dendritic cell (ITGAX/CD11C, FCER1A), Th2 (IL‐13, CCL17, TNFRSF4/OX40), and Th17 (CCL20, CXCL1) products, while biopsies showed higher upregulation of Th22 associated genes (IL‐22, S100As) and dermal cytokines (IFN‐γ, CCL26). Itch‐related genes (IL‐31, TRPV3) were preferentially captured by tape‐strips. Epidermal barrier abnormalities were detected in both techniques, with terminal differentiation defects (FLG2, PSORS1C2) better represented by tape‐strips and epidermal hyperplasia changes (KRT16, MKI67) better detected by biopsies. Conclusions: Tape‐strips and biopsies capture overlapping but distinct features of the AD molecular signature, suggesting their respective utility for monitoring specific AD‐related immune, itch, and barrier abnormalities in clinical trials and longitudinal studies. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions While B‐cells have historically been implicated in allergy development, a growing body of evidence supports their role in atopic dermatitis (AD). B‐cell differentiation across ages in AD, and its relation to disease severity scores, has not been well defined.To compare the frequency of B‐cell subsets in blood of 0–5, 6–11, 12–17, and ≥18 years old patients with AD versus age‐matched controls.Flow cytometry was used to measure B‐cell subset frequencies in the blood of 27 infants, 17 children, 11 adolescents, and 31 adults with moderate‐to‐severe AD and age‐matched controls. IgD/CD27 and CD24/CD38 core gating systems and an 11‐color flow cytometry panel were used to determine frequencies of circulating B‐cell subsets. Serum total and allergen‐specific IgE (sIgEs) levels were measured using ImmunoCAP®.Adolescents with AD had lower frequencies of major B‐cells subsets (p < .03). CD23 expression increased with age and was higher in AD compared to controls across all age groups (p < .04). In AD patients, multiple positive correlations were observed between IL‐17‐producing T‐cells and B‐cell subsets, most significantly non‐switched memory (NSM) B‐cells (r = .41, p = .0005). AD severity positively correlated with a list of B‐cell subsets (p < .05). IL‐9 levels gradually increased during childhood, reaching a peak in adolescence, paralleling allergen sensitization, particularly in severe AD. Principal component analysis of the aggregated environmental sIgE data showed that while controls across all ages tightly clustered together, adolescents with AD demonstrated distinct clustering patterns relative to controls.Multiple correlations between B‐cells and T‐cells, as well as disease severity measures, suggest a complex interplay of immune pathways in AD. Unique B‐cell signature during adolescence, with concurrent allergen sensitization and IL‐9 surge, point to a potentially wider window of opportunity to implement interventions that may prevent the progression of the atopic march. [ABSTRACT FROM AUTHOR]

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory disease with a considerable disease burden. Existing treatment options are limited and often suboptimal; a high unmet need exists for effective targeted therapies., Objective: To explore the effects of spesolimab treatment in patients with HS., Methods: This randomized, double-blind, placebo-controlled, proof-of-clinical-concept study was conducted at 25 centers across 12 countries from May 3, 2021, to April 21, 2022. Patients had moderate-to-severe HS for ≥1 year before enrollment. Patients were randomized (2:1) to receive a loading dose of 3600 mg intravenous spesolimab (1200 mg at Weeks 0, 1, and 2) or matching placebo, followed by maintenance with either 1200 mg subcutaneous spesolimab every 2 weeks from Week 4-10 or matching placebo. The primary endpoint was the percentage change from baseline in total abscess and inflammatory nodule (AN) count at Week 12. Secondary endpoints were the absolute change from baseline in International Hidradenitis Suppurativa Severity Score System (IHS4), percentage change from baseline in draining tunnel (dT) count, the proportion of patients achieving a dT count of zero, absolute change from baseline in revised Hidradenitis Suppurativa Area and Severity Index (HASI-R), the proportion of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR50), the proportion of patients with ≥1 flare (all at Week 12), and patient-reported outcomes (PROs)., Results: In this completed trial, randomized patients (N=52) received spesolimab (n=35) or placebo (n=17). The difference (95% confidence interval) versus placebo in least squares mean are reported. At Week 12, the percentage change in total AN count was similar between treatment arms: -4.1% (-31.7, 23.4). There was greater numerical improvement in the spesolimab arm, as measured by IHS4: -13.9 (-25.6, -2.3); percentage change from baseline in dT count: -96.6% (-154.5, -38.8); and the proportion of patients achieving a dT count of zero: 18.3% (-7.9, 37.5). Spesolimab treatment also improved HASI-R and HiSCR50 versus placebo. Spesolimab demonstrated a favorable safety profile, similar to that observed in trials in other diseases., Conclusions: This exploratory proof-of-clinical-concept study supports the development of spesolimab as a new therapeutic option in HS. ClinicalTrials.gov identifier: NCT04762277., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)