Comparative molecular analysis of IL-17A and IL-23 pathway inhibition in moderate-to-severe psoriasis: 4-week results from IXORA-R.

Ixekizumab, an IL-17A antagonist, and guselkumab, an IL-23p19 antagonist, are common psoriasis treatments. This longitudinal analysis assessed gene expression profiles in ixekizumab- and guselkumab-treated patients with plaque psoriasis through Week 4. In IXORA-R (NCT03573323), a head-to-head Phase 4 study, adults with moderate-to-severe plaque psoriasis were assigned 1:1 to receive ixekizumab or guselkumab.

A basophil-fibroblast pro-inflammatory axis fuels type 2 skin inflammation.

Chronic inflammatory skin diseases arise from dysregulated interactions between tissue-resident and infiltrating cells, the complexity of which hinders disease understanding and treatment. To address this, here, we present a single-cell spatiotemporal atlas of murine type 2 skin inflammation using MERFISH and scRNA-seq. Analyzing ∼430,000 cells during MC903- and oxazolone-induced dermatitis, we identify 39 cell types, including pro-inflammatory fibroblasts that resemble those in human atopic dermatitis.

Targeting the IL-36 receptor with spesolimab mitigates residual inflammation and prevents generalized pustular psoriasis flares.

People with generalized pustular psoriasis experience underlying skin inflammation, even in the absence of flares. Spesolimab treatment helps control the inflammation and prevent future flares.

Guselkumab binding to CD64 IL-23-producing myeloid cells enhances potency for neutralizing IL-23 signaling.

IL-23 is implicated in the pathogenesis of immune-mediated inflammatory diseases, and myeloid cells that express Fc gamma receptor 1 (FcγRI or CD64) on their surface have been recently identified as a primary source of IL-23 in inflamed tissue. Our complementary analyses of transcriptomic datasets from psoriasis and IBD showed increased expression of CD64 and IL-23 transcripts in inflamed tissue, and greater abundance of cell types with co-expression of CD64 and IL-23. These findings led us to explore potential implications of CD64 binding on the function of IL-23-targeting monoclonal antibodies (mAbs).

Psoriasis harbors multiple pathogenic type 17 T-cell subsets: Selective modulation by risankizumab.

Background: Recent single-cell studies indicated that IL-17-producing T cells (T17) have diverse subsets expressing IL-17A, IL-17F, or a combination in human psoriasis skin. However, it is unknown how T17 subsets are differently regulated by IL-23 versus IL-17A blockade.

Objective: We sought to investigate how systemic monoclonal antibody injections blocking IL-23 versus IL-17A differently modify immune cell transcriptomes in human psoriasis skin.

To increase trust in clinical research: Be worthy of trust and enhance the role of clinical research nurses.

There has been an erosion of trust in medical care and clinical research, and this has raised issues about whether institutions and investigators conducting clinical research are worthy of trust. We review recent literature on research on trust and trustworthiness in the clinical research enterprise and identify opportunities to enhance trustworthiness, which will likely increase participant trust in clinical research. In addition, we review materials reporting the results of national polls related to the public's trust in different occupations.

Skin immune-mesenchymal interplay within tertiary lymphoid structures promotes autoimmune pathogenesis in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by keratinized epithelial tunnels that grow deeply into the dermis. Here, we examined the immune microenvironment within human HS lesions. Multi-omics profiling and multiplexed imaging identified tertiary lymphoid structures (TLSs) near HS tunnels.

International Dermatology Outcome Measures (IDEOM): A Report From the 2023 Annual Meeting.

Background: International Dermatology Outcome Measures (IDEOM) is a non-profit organization whose mission is to improve the availability of evidence-based, consensus-driven outcome measures for dermatological diseases. IDEOM facilitates collaboration between stakeholders from various backgrounds, including researchers, patients, physicians, and industry representatives, to develop objective benchmark metrics that enable better treatment and management of dermatologic conditions.

Summary: The 2023 IDEOM Annual Meeting was held June 23-24, 2023.

Pharmacodynamic Response to Deucravacitinib, an Oral, Selective, Allosteric TYK2 Inhibitor, in a Global, Phase 2, Randomized, Double-Blind, Placebo-Controlled Psoriasis Trial.

Background: Psoriasis, a chronic, immune-mediated, inflammatory disease, affects 2‒3% of the population. Tyrosine kinase 2 (TYK2) mediates cytokine signaling involved in adaptive [interleukin (IL)-12, IL-23] and innate (type-I interferons) immune responses; IL-23-driven T-helper (Th)17 pathways play a key role in chronic inflammation in psoriasis. In a phase 2 trial, deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, reduced IL-23/Th17 and type-I interferon pathway expression in the skin of patients with moderate to severe plaque psoriasis, reductions that were accompanied by clinical improvement of psoriatic lesions.

The Impact of Melanoma Imaging Biomarker Cues on Detection Sensitivity and Specificity in Melanoma versus Clinically Atypical Nevi.

Incorporation of dermoscopy and artificial intelligence (AI) is improving healthcare professionals' ability to diagnose melanoma earlier, but these algorithms often suffer from a "black box" issue, where decision-making processes are not transparent, limiting their utility for training healthcare providers. To address this, an automated approach for generating melanoma imaging biomarker cues (IBCs), which mimics the screening cues used by expert dermoscopists, was developed. This study created a one-minute learning environment where dermatologists adopted a sensory cue integration algorithm to combine a single IBC with a risk score built on many IBCs, then immediately tested their performance in differentiating melanoma from benign nevi.

Differential Pharmacodynamic Effects on Psoriatic Biomarkers by Guselkumab Versus Secukinumab Correlate with Long-Term Efficacy: An ECLIPSE Substudy.

IL-23 is a cytokine produced by myeloid cells that drives the T helper 17 pathway and plays an essential role in the pathophysiology of plaque psoriasis. IL-23 activation initiates a cascade of cytokines subsequently inducing the expression of many psoriasis-related proteins. This study aimed to better understand the underlying mechanisms driving the differences between IL-23 and IL-17A blockade in patients with psoriasis and their implications for durability of clinical responses.

Hepatocyte Growth Factor Has Unique Functions in Keratinocytes that Differ from those of IL-17A and TNF and May Contribute to Inflammatory Pathways in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease that is difficult to control, and its mechanism remains unclear. Hepatocyte GF (HGF) has been reported to be significantly upregulated in the serum and skin of patients with HS, especially in the lesions with tunnels. In this study, we examined the transcriptome of HGF-treated keratinocytes and compared it with genetic profiling of HS lesions.

Spesolimab Reduces Inflammation in Generalized Pustular Psoriasis: Molecular Characterization of Flare Treatment in EFFISAYIL 1.

EFFISAYIL 1 was a randomized, placebo-controlled study of spesolimab, an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare. Treatment with spesolimab led to more rapid pustular and skin clearance versus treatment with placebo in approximately half of the patients. In this study, we present histologic, transcriptomic, and proteomic analyses of lesional and nonlesional skin and whole-blood samples collected from EFFISAYIL 1.

Evolution of pathologic B-cell subsets and serum environment-specific sIgEs in patients with atopic dermatitis and controls, from infancy to adulthood.

Background: 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.

Objective: 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.

Eosinophils in hidradenitis suppurativa patients exhibit pro-inflammatory traits, implicating a potential pathogenic role in the disease.

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.

The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus.

The autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure can lead to development of inflammatory skin lesions. We have previously shown that Langerhans cells (LCs) limit keratinocyte apoptosis and photosensitivity via a disintegrin and metalloprotease 17 (ADAM17)-mediated release of epidermal growth factor receptor (EGFR) ligands and that LC ADAM17 sheddase activity is reduced in lupus. Here, we sought to understand how the lupus skin environment contributes to LC ADAM17 dysfunction and, in the process, differentiate between effects on LC ADAM17 sheddase function, LC ADAM17 expression, and LC numbers.

IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy.

Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. We propose studies to advance IL-23 biology and unravel differences in response to anti-IL-23 therapy.

Gram-negative anaerobes elicit a robust keratinocytes immune response with potential insights into HS pathogenesis.

Hidradenitis Suppurativa (HS) is a chronic autoinflammatory skin disease with activated keratinocytes, tunnel formation and a complex immune infiltrate in tissue. The HS microbiome is polymicrobial with an abundance of commensal gram-positive facultative (GPs) Staphylococcus species and gram-negative anaerobic (GNA) bacteria like Prevotella, Fusobacterium and Porphyromonas with increasing predominance of GNAs with disease severity. We sought to define the keratinocyte response to bacteria commonly isolated from HS lesions to probe pathogenic relationships between HS and the microbiome.

Targeted review of mutations in patients with generalised pustular psoriasis.

Background: Generalised pustular psoriasis (GPP) is a rare and chronic skin disease historically treated with therapies that were originally intended to treat plaque psoriasis (PsO). However, GPP and plaque PsO have distinct pathogeneses and clinical courses.

Objectives: This study aimed to further characterise the unique genetic background of GPP by summarising evidence on the frequency and type of 6RN gene mutation, a gene that normally suppresses proinflammatory responses, in patients with GPP compared to patients with GPP and plaque PsO, and patients with plaque PsO only.

Proof-of-concept study exploring the effect of spesolimab in patients with moderate-to-severe hidradenitis suppurativa: a randomized double-blind placebo-controlled clinical trial.

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a considerable disease burden. Existing treatment options are limited and often suboptimal; a high unmet need exists for effective targeted therapies.

Objectives: To explore the effects of spesolimab treatment in patients with HS.