Background: The etiology and different inflammatory steps associated with the development of an acne nodule remain unsolved. Objectives: This study aimed to investigate the main biological processes involved in acne nodules and compare them to those of papules. Methods: Nodules, papules, and non-involved skin of the back (control) were biopsied to perform proteomic analysis using mass spectrometry, Luminex assay, and elastase staining on skin sections. Results: Many factors involved in the migration and function of immune cells, particularly those impacting leukocytes and neutrophils, were strongly and significantly higher in nodules than in papules and non-involved skin, while several enzymes involved in lipid metabolism were lower. Elastase staining confirmed strong neutrophil infiltration within and around the nodules. Conclusions: Our results highlight the role of neutrophils during nodule formation in severe nodular acne of the back.

With possible implications in multiple autoimmune diseases, the retinoic acid receptor‐related orphan receptor RORγ has become a sought‐after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N‐(2,4‐dimethylphenyl)‐N‐isobutyl‐2‐oxo‐1‐[(tetrahydro‐2H‐pyran‐4‐yl)methyl]‐2,3‐dihydro‐1H‐benzo[d]imidazole‐5‐sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL‐23‐induced mouse skin inflammation model.

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B . Risk alleles at the 1q25 locus are associated with increased expression of LAMC2 , in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne.

Possible outcomes of acne lesions are atrophic scars, which may cause serious psychological distress. Current treatments for postacne scarring often require invasive procedures. Pathophysiological studies on acne scarring have only investigated the first week of papule life.

First‐ and third‐generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) γ, expressed in the epidermis and infundibulum.

First- and third-generation retinoids even though efficacious in acne, lack full selectivity for RARγ expressed in the epidermis and infundibulum. We describe the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. Trifarotene is a selective RARγ agonist with >20-fold selectivity over RARa and RARβ. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0.01% applied topically is highly comedolytic and has antiinflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, RA metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after four weeks of topical application of trifarotene 0.005% cream. Based on its RARg selectivity, rapid degradation in human hepatic microsomes and pharmacological properties including potent modulation of epidermal processes, topical treatment with trifarotene could result in good efficacy and may present a favorable safety profile in acne and ichthyotic disorders.

Acne is a chronic inflammatory skin disease, linked to changes in hormone levels. It mainly affects adolescents and young adults, and may lead to permanent scarring. 1.5 billion people aged between 15 and 45 suffer from some form of acne – mild, moderate or severe. Retinoic acid is one type of treatment for acne, and there are several different types, which are applied directly to the skin (topically). Trifarotene is a new type of retinoic acid which is able to act against only one particular retinoic acid receptor, and this study looked at whether it might be suitable for use in acne and other skin diseases, and potentially have an improved efficacy and safety profile compared with less selective retinoids (i.e. ones that target more than one retinoic acid receptor). Looking at the biological pathways of the drug, the authors suggest that it should be very effective in acne. Furthermore, trifarotene is expected to be rapidly eliminated in the blood stream, thereby potentially leading to fewer side effects and making it particularly useful for the treatment of large skin surface areas, such as the back and chest of acne patients. Based on these favourable characteristics of trifarotene, it is worth now investigating the clinical efficacy of this retinoid.

痤疮是一种慢性炎症性皮肤病,与激素水平变动有关。它主要影响青少年和年轻人,可能导致永久性疤痕。15亿15岁至45岁之间的人群曾患上某种形式的痤疮 ‐ 轻度、中度或重度。视黄酸是痤疮的一类治疗方法,存在多种不同类型,可直接敷用在皮肤上(局部)。Trifarotene是新型视黄酸,能够只针对一种特定的视黄酸受体起作用,而本研究调查了它是否适用于痤疮和其他皮肤疾病,并且与选择性更低的视黄酸(即针对多个视黄酸受体)相比是否可能改善疗效和安全性。通过调查药物的生物学途径,作者表示,该药物应该对痤疮非常有效。此外,trifarotene将在血流中迅速消失,因此可能会减少副作用,使其特别适用于治疗大面积的皮肤表面部位,比如痤疮患者的背部和颈部。基于trifarotene的这些有利特征,此视黄酸的临床效果目前很值得研究。

Rosacea is a chronic inflammatory skin disease of the face. The objective of the studies described here was to evaluate the efficacy of clindamycin in the treatment of rosacea. Two multicenter, randomized, vehicle-controlled, phase 2 studies were conducted in participants with moderate to severe rosacea. Study A was a 12-week dose-comparison, 5-arm, parallel group comparison of clindamycin cream 1% or vehicle once or twice daily and clindamycin cream 0.3% once daily. Study B was a 2-arm comparison of twice daily clindamycin gel 1% versus vehicle gel. A total of 629 participants (study A, N=416; study B, N=213) were randomized. The results of these studies indicated that clindamycin cream 0.3% and 1% and clindamycin gel 1% were no more effective than the vehicle in the treatment of moderate to severe rosacea, suggesting clindamycin has no intrinsic anti-inflammatory activity in rosacea.

BACKGROUND:Protein expression is disturbed in the psoriatic stratum corneum (SC). Noninvasive methods for the description of pathophysiological changes and drug profiling in psoriasis are desirable.OBJECTIVES:Undertake large-scale noninvasive protein expression studies in psoriatic SC to identify biomarkers of pathophysiological processes and use them for drug profiling.METHODS:Psoriatic SC was harvested through repetitive tape-stripping. Nonlesional and lesional SC, as well as vehicle-treated and drug-treated lesional SC samples were collected. Protein extracts from nonlesional and lesional skin biopsies were used for comparison. Calcipotriol-betamethasone (CB) was used as a reference medication. Proteins extracted from pooled tape strips were quantified using mass spectrometry (MS), Western blotting, enzyme-linked immunosorbent assay and Luminex technologies.RESULTS:MS-based methods identified 140 proteins differentially expressed in psoriatic SC. Epidermis development, glycolysis, regulation of apoptosis, cytoskeleton organization and peptide cross-linking were modulated, all reflecting perturbed epidermal differentiation. Using antibody-based techniques, increased levels of sICAM1, of CXCL1- and CXCL8-attracting neutrophils, of CXCL10- and CCL4-attracting T helper (Th) 1 cells, and of CCL2- and CCL4-attracting monocytes and dendritic cells were observed. Quantification of the Th1 and Th17 markers tumour necrosis factor, interleukin (IL) 12B, IL17A and IL17F in lesional SC was successful, while the Th2 cytokines IL4, IL5 and IL13, not involved in the disease process, were not detected. The pruritic cytokine IL31 was detected in lesional SC. CXCL1, CXCL8, CXCL10 and sICAM were used to investigate disease remission, ranking three topical treatments according to their known clinical efficacy.CONCLUSIONS:Protein biomarker quantification in psoriatic SC detects key pathophysiological mechanisms and enables noninvasive drug profiling in translational medicine settings.

The stratum corneum plays a crucial role in barrier function and is under investigation in several skin pathologies. The stratum corneum (SC) of atopic xerosis (AX) reveals not only decreased hydration but also mildly impaired barrier function characterized by an increase in Trans Epidermal Water Loss (TEWL), elevated pH values, and an increased turnover rate of the SC consisting of thick layers of smaller-sized corneocytes. The mildly impaired SC functions of AX can be improved by daily repeated applications of effective moisturizers, which are effective in preventing the progression of AX to atopic dermatitis (AD). In a recent study, clinical and biophysical observations were in favour of an improvement of skin surface after 8 daily applications of Excipial (anti-itch foam). In AX the effect of moisturizers in general on the stratum corneum protein composition has not yet been fully analysed. Mass spectrometry analysis was performed using protein extracted from stratum corneum collected before and 48h after 8 days of Excipial application. More than 400 proteins were identified in SC. Several proteins were found significantly modulated after Excipial treatment. We found a significant increase in content of proteins involved in cohesion of the SC and its barrier function, such as Desmoplakin and the Keratin type II cytoskeletal 2 and in regulation of epidermal homeostasis, such as filaggrin-2. In addition, we found two abundant unique peptides of serum albumin slightly but significantly decreased after treatment. Using Luminex technology a slight decrease in serum albumin content was observed (fold: -1.5, p <0.05). Interestingly, albumin was previously described up-regulated in AD. Taken together, our proteomics data indicate that skin homeostasis and barrier function in AX was improved at the molecular level after 8 days Excipial application.

Rosacea is a common chronic inflammatory skin disease of unknown etiology. Our knowledge about an involvement of the adaptive immune system is very limited. We performed detailed transcriptome analysis, quantitative real-time reverse-transcriptase-PCR, and quantitative immunohistochemistry on facial biopsies of rosacea patients, classified according to their clinical subtype. As controls, we used samples from patients with facial lupus erythematosus and healthy controls. Our study shows significant activation of the immune system in all subtypes of rosacea, characterizing erythematotelangiectatic rosacea (ETR) already as a disease with significant influx of proinflammatory cells. The T-cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFN-γ or IL-17, for example. Chemokine expression patterns support a Th1/Th17 polarization profile of the T-cell response. Macrophages and mast cells are increased in all three subtypes of rosacea, whereas neutrophils reach a maximum in papulopustular rosacea. Our studies also provide evidence for the activation of plasma cells with significant antibody production already in ETR, followed by a crescendo pattern toward phymatous rosacea. In sum, Th1/Th17 polarized inflammation and macrophage infiltration are an underestimated hallmark in all subtypes of rosacea. Therapies directly targeting the Th1/Th17 pathway are promising candidates in the future treatment of this skin disease.

Acne vulgaris (acne) is a common inflammatory disorder of the cutaneous pilo-sebaceous unit. Here we perform a genome-wide association analysis in the United Kingdom, comparing severe cases of acne (n=1,893) with controls (n=5,132). In a second stage, we genotype putative-associated loci in a further 2,063 acne cases and 1,970 controls. We identify three genome-wide significant associations: 11q13.1 (rs478304, Pcombined=3.23 × 10−11, odds ratio (OR)=1.20), 5q11.2 (rs38055, Pcombined=4.58 × 10−9, OR=1.17) and 1q41 (rs1159268, Pcombined=4.08 × 10−8, OR=1.17). All three loci contain genes linked to the TGFβ cell signalling pathway, namely OVOL1, FST and TGFB2. Transcripts of OVOL1 and TFGB2 have decreased expression in affected compared with normal skin. Collectively, these data support a key role for dysregulation of TGFβ-mediated signalling in susceptibility to acne. Acne vulgarisis a common, inflammatory skin disorder. Here the authors carry out a genome-wide association study and identify three genetic variants that associate with an increased risk of developing acne, which together suggest a mechanistic role for the TGFβ cell signalling pathway in acne development and progression.

The mechanisms of inflammation in acne are currently subject of intense investigation. This study focused on the activation of adaptive and innate immunity in clinically early visible inflamed acne lesions and was performed in two independent patient populations. Biopsies were collected from lesional and non-lesional skin of acne patients. Using Affymetrix Genechips, we observed significant elevation of the signature cytokines of the Th17 lineage in acne lesions compared to non-lesional skin. The increased expression of IL-17 was confirmed at the RNA and also protein level with real-time PCR (RT-PCR) and Luminex technology. Cytokines involved in Th17 lineage differentiation (IL-1β, IL-6, TGF-β, IL23p19) were remarkably induced at the RNA level. In addition, proinflammatory cytokines and chemokines (TNF-α, IL-8, CSF2 and CCL20), Th1 markers (IL12p40, CXCR3, T-bet, IFN-γ), T regulatory cell markers (Foxp3, IL-10, TGF-β) and IL-17 related antimicrobial peptides (S100A7, S100A9, lipocalin, hBD2, hBD3, hCAP18) were induced. Importantly, immunohistochemistry revealed significantly increased numbers of IL-17A positive T cells and CD83 dendritic cells in the acne lesions. In summary our results demonstrate the presence of IL-17A positive T cells and the activation of Th17-related cytokines in acne lesions, indicating that the Th17 pathway is activated and may play a pivotal role in the disease process, possibly offering new targets of therapy.