Inflammasome Activation by Propionibacterium acnes: The Story of IL-1 in Acne Continues to Unfold

Insights into the immune mechanisms at play in skin diseases including acne continue to be made. In this issue, Kistowska et al. confirm that Propionibacterium acnes activates inflammasomes leading to the production of IL-1β and they further identify putative mechanisms by which this process occurs. These data raise interesting questions regarding a multipronged approach by which P. acnes elicits inflammation in early versus late acne and putative differences in the effects of IL-1α and IL-1β in this disease process

IL-17: A Key Player in the P. acnes Inflammatory Cascade?

Recent advances in our understanding of inflammatory skin diseases now afford an opportunity to delve deeper into microbial/host interactions in acne. Agak et al. report that Propionibacterium acnes induces IL-17 expression in peripheral blood mononuclear cells and present new evidence that IL-17+ cells are found in the perifollicular infiltrate of comedones. Additional studies are needed to assess the clinical relevance of IL-17 in acne

Insulin-Like Growth Factor-1 Induces Lipid Production in Human SEB-1 Sebocytes Via Sterol Response Element-Binding Protein-1

An understanding of the molecular signaling involved in sebaceous gland lipid production is needed to develop therapeutic targets to improve acne. Treatment with methylisobutylxanthine, dexamethasone, and a high dose of insulin (MDI) has been shown to differentiate 3T3-L1 preadipocytes into adipocytes, a differentiation marked by an increase in lipid production. The present study has the following aims: (1) Since high doses of insulin, as found in MDI, will activate the IGF-1 receptor, we sought to determine if IGF-1 is capable of reproducing the lipogenic effect seen with MDI treatment, and (2) to determine if the sterol response element-binding protein-1 (SREBP-1) pathway mediates the increase in lipogenesis. Here we report that MDI increases lipogenesis and that this effect can be attributed wholly to the high-dose insulin in SEB-1 cells. Further, we show that a physiologically relevant dose of IGF-1 or high-dose (1μm) insulin induces an increase in SREBP-1 mRNA, protein, and total lipid production; while 100nm insulin induces lipogenesis yet the SREBP protein levels remain unchanged. These data indicate that activation of the IGF-1 receptor increases lipogenesis in SEB-1 cells through both SREBP-dependent and SREBP-independent pathways

G2A Attenuates Propionibacterium acnes Induction of Inflammatory Cytokines in Human Monocytes.

Background:Acne vulgaris is a disease of the pilosebaceous unit characterized by increased sebum production, hyperkeratinization, and immune responses to Propionibacterium acnes (PA). Here, we explore a possible mechanism by which a lipid receptor, G2A, regulates immune responses to a commensal bacterium. Objective:To elucidate the inflammatory properties of G2A in monocytes in response to PA stimulation. Furthermore, our study sought to investigate pathways by which lipids modulate immune responses in response to PA. Methods:Our studies focused on monocytes collected from human peripheral blood mononuclear cells, the monocytic cell line THP-1, and a lab strain of PA. Our studies involved the use of enzyme-linked immunosorbent, Western blot, reverse transcription polymerase chain reaction, small interfering RNA (siRNA), and microarray analysis of human acne lesions in the measurements of inflammatory markers. Results:G2A gene expression is higher in acne lesions compared to normal skin and is inducible by the acne therapeutic, 13-cis-retinoic acid. In vitro, PA induces both the Toll-like receptor 2-dependent expression of G2A as well as the production of the G2A ligand, 9-hydroxyoctadecadienoic acid, from human monocytes. G2A gene knockdown through siRNA enhances PA stimulation of interleukin (IL)-6, IL-8, and IL-1β possibly through increased activation of the ERK1/2 MAP kinase and nuclear factor kappa B p65 pathways. Conclusion:G2A may play a role in quelling inflammatory cytokine response to PA, revealing G2A as a potential attenuator of inflammatory response in a disease associated with a commensal bacterium

Randomized phase 3 evaluation of trifarotene 50 μg/g cream treatment of moderate facial and truncal acne.

BACKGROUND: Acne vulgaris often affects the face, shoulders, chest, and back, but treatment of nonfacial acne has not been rigorously studied. OBJECTIVES: Assess the safety and efficacy of trifarotene 50 μg/g cream, a novel topical retinoid, in moderate facial and truncal acne. METHODS: Two phase III double-blind, randomized, vehicle-controlled, 12-week studies of once-daily trifarotene cream versus vehicle in subjects aged 9 years or older. The primary end points were rate of success on the face, as determined by the Investigator\u27s Global Assessment (clear or almost clear and ≥2-grade improvement), and absolute change from baseline in inflammatory and noninflammatory counts from baseline to week 12. The secondary end points were rate of success on the trunk (clear or almost clear and ≥2-grade improvement) and absolute change in truncal inflammatory and noninflammatory counts from baseline to week 12. Safety was assessed through adverse events, local tolerability, vital signs, and routine laboratory testing results. RESULTS: In both studies, at week 12 the facial success rates according to the Investigator\u27s Global Assessment and truncal Physician\u27s Global Assessment and change in inflammatory and noninflammatory lesion counts (both absolute and percentage) were all highly significant (P \u3c .001) in favor of trifarotene when compared with the vehicle. LIMITATIONS: Adjunctive topical or systemic treatments were not studied. CONCLUSION: These studies demonstrate that trifarotene appears to be safe, effective, and well tolerated in treatment of both facial and truncal acne

Patient experiences with oily skin: The qualitative development of content for two new patient reported outcome questionnaires

<p>Abstract</p> <p>Objective</p> <p>To develop the content for two new patient reported outcome (PRO) measures to: a) assess the severity of symptoms; and b) the impact of facial skin oiliness on emotional wellbeing using qualitative data from face to face, and internet focus groups in Germany and the US.</p> <p>Methods</p> <p>Using input from initial treatment satisfaction focus groups (n = 42), a review of relevant literature and expert clinicians (n = 3), a discussion guide was developed to guide qualitative inquiry using Internet focus groups (IFGs). IFGs were conducted with German (n = 26) and US (n = 28) sufferers of oily skin. Questionnaire items were generated using coded transcript data from the focus groups. Cognitive debriefing was conducted online with 42 participants and face to face with an additional five participants to assess the comprehension of the items.</p> <p>Results</p> <p>There were equal numbers of male and female participants; mean age was 35.4 (SD 9.3) years. On average, participants had had oily skin for 15.2 years, and 74% (n = 40) reported having mild-moderate acne. Participants reported using visual, tactile and sensory (feel without touching their face) methods to evaluate the severity of facial oiliness. Oily facial skin had both an emotional and social impact, and was associated with feelings of unattractiveness, self-consciousness, embarrassment, irritation and frustration. Items were generated for a measure of oily skin severity (Oily Skin Self-Assessment Scale) and a measure of the impact of oily skin on emotional well-being (Oily Skin Impact Scale). Cognitive debriefing resulted in minor changes to the draft items and confirmed their face and content validity.</p> <p>Conclusion</p> <p>The research provides insight into the experience of having oily skin and illustrates significant difficulties associated with the condition. Item content was developed for early versions of two PRO measures of the symptoms and emotional impact of oily facial skin. The psychometric validation of these measures reported elsewhere.</p

Identifying gaps and providing recommendations to address shortcomings in the investigation of acne sequelae by the Personalising Acne: Consensus of Experts panel

Background: The physical sequelae of acne include erythema, hyperpigmentation, and scarring, which are highly burdensome for patients. Early, effective treatment can potentially limit and prevent sequelae development, but there is a need for guidance for and evidence of prevention-oriented management to improve patient outcomes. Objective: To identify unmet needs of acne sequelae and generate expert recommendations to address gaps in clinical guidance. Methods: The Personalizing Acne: Consensus of Experts panel of 13 dermatologists used a modified Delphi approach to achieve a consensus on the clinical aspects of acne sequelae. A consensus was defined as ≥75% of the dermatologists voting agree or strongly agree. All voting was electronic and blinded. Results: The panel identified gaps in current guidance and made recommendations related to acne sequelae. These included identification and classification of sequelae, pertinent points to consider for patient consultations, and management aimed at reducing the development of sequelae. Limitations: The recommendations are based on expert opinion and made in the absence of high-quality evidence. Conclusions: The identified gaps should help inform future research and guideline development for acne sequelae. The consensus-based recommendations should also support the process of consultations throughout the patient journey, helping to reduce the development and burden of acne sequelae through improved risk factor recognition, early discussion, and appropriate management

The Personalised Acne Care Pathway-Recommendations to guide longitudinal management from the Personalising Acne: Consensus of Experts

Background: Acne is a chronic disease with a varying presentation that requires long-term management. Despite this, the clinical guidelines for acne offer limited guidance to facilitate personalized or longitudinal management of patients. Objectives: To generate recommendations to support comprehensive, personalized, long-term patient management that address all presentations of acne and its current and potential future burden. Methods: The Personalising Acne: Consensus of Experts panel consisted of 13 dermatologists who used a modified Delphi approach to reach consensus on statements related to longitudinal acne management. The consensus was defined as ≥75% voting agree or strongly agree. All voting was electronic and blinded. Results: Key management domains, consisting of distinct considerations, points to discuss with patients, and pivot points were identified and incorporated into the Personalised Acne Care Pathway. Long-term treatment goals and expectations and risk of (or fears about) sequelae are highlighted as particularly important to discuss frequently with patients. Limitations: Recommendations are based on expert opinion, which could potentially differ from patients\u27 perspectives. Regional variations in health care systems may not have been captured. Conclusions: The Personalised Acne Care Pathway provides practical recommendations to facilitate the longitudinal management of acne, which can be used by health care professionals to optimize and personalize care throughout the patient journey