Treatment response to isotretinoin correlates with specific shifts in Cutibacterium acnes strain composition within the follicular microbiome.

There are no drugs as effective as isotretinoin for acne. Deciphering the changes in the microbiome induced by isotretinoin in the pilosebaceous follicle of successfully treated patients can pave the way to identify novel therapeutic alternatives. We determined how the follicular microbiome changes with isotretinoin and identified which alterations correlate with a successful treatment response. Whole genome sequencing was done on casts from facial follicles of acne patients sampled before, during and after isotretinoin treatment. Alterations in the microbiome were assessed and correlated with treatment response at 20 weeks as defined as a 2-grade improvement in global assessment score. We investigated the α-diversity, ß-diversity, relative abundance of individual taxa, Cutibacterium acnes strain composition and bacterial metabolic profiles with a computational approach. We found that increased ß-diversity of the microbiome coincides with a successful treatment response to isotretinoin at 20 weeks. Isotretinoin selectively altered C. acnes strain diversity in SLST A and D clusters, with increased diversity in D1 strains correlating with a successful clinical response. Isotretinoin significantly decreased the prevalence of KEGG Ontology (KO) terms associated with four distinct metabolic pathways inferring that follicular microbes may have limited capacity for growth or survival following treatment. Importantly, these alterations in microbial composition or metabolic profiles were not observed in patients that failed to achieve a successful response at 20 weeks. Alternative approaches to recapitulate this shift in the balance of C. acnes strains and microbiome metabolic function within the follicle may be beneficial in the future treatment of acne.

Anti-IL-17A blockade did not significantly reduce inflammatory lesions in a placebo-controlled pilot study in adult patients with moderate to severe acne.

BACKGROUND: CJM112 is a potent anti-IL-17A monoclonal antibody, whose clinical efficacy in psoriasis was recently documented. This study aimed to assess the effect of IL-17A blockade, using CJM112, in patients with moderate to severe acne. METHODS: A randomized, placebo-controlled, double-blind, parallel-group, proof-of-concept study was conducted on patients with moderate to severe acne. Patients received CJM112 300 mg, 75 mg, or placebo subcutaneously during Treatment Period 1 (0-12 weeks). Patients receiving placebo were re-randomized to receive CJM112 300 mg or 75 mg during Treatment Period 2 (12-24 weeks). The primary endpoint was the number of inflammatory facial lesions at Week 12. RESULTS: As the futility criterion was met during the interim analysis, only 52/75 (69.3%) patients were recruited. In total, 48/52 (92.3%) and 26/41 (63.4%) completed Treatment Periods 1 and 2, respectively. All groups exhibited a reduction in facial inflammatory lesions, with no difference observed between CJM112 and placebo (CJM112 300 mg 27.6 ± 20.7; CJM112 75 mg 30.4 ± 34.8; placebo 23.6 ± 13.6; primary endpoint). Additionally, no differences were observed between groups in other secondary and exploratory endpoints at Week 12. CONCLUSIONS: Anti-IL-17A therapy was not significantly different compared to the placebo in reducing inflammatory lesions in patients with moderate to severe acne.

Keeping the peace: commensal Cutibacterium acnes trains CD4+ TH17 cells to trap and kill.

Commensal or pathogenic bacterial communities of the skin interact with the host immune system to preserve homeostasis or sustain disease. In this issue of the JCI, Agak et al. substantially advance our conceptual understanding of TH17 cell biology. The researchers identified IL-26-independent mechanisms by which CD4+ TH17 clones directly kill bacteria. These CD4+ TH17 clones share antimicrobial properties with cytotoxic T cells and granulocytes as evidenced by secretion of granulysin, granzyme B, and histone-laden DNA extracellular traps. Interestingly, these clones emerged following monocyte education by Cutibacterium acnes strains associated with healthy skin, but not those associated with acne. Overall, the antimicrobial mechanisms employed by these TH17 subsets suggest a unique link between innate and adaptive immune responses.

Building a System to Engage and Sustain Research Careers for Physicians.

There are increasing needs for physician-investigators to translate the rapid expansion of knowledge, technology/interventions, and big data into the clinical realm at a time of increasing age-related disabilities and communicable diseases. Yet, the number of physician-investigators has continued to decline, and only a small number of medical school graduates in the United States are actively engaged in research. This problem may be particularly pronounced in small- and medium-sized academic institutions due to more limited educational and mentoring infrastructure. Neither efforts by the federal government nor isolated institutional programs alone have been effective yet in solving this problem. This article describes an integrated institutional strategy undertaken at Penn State College of Medicine that is focused on developing and sustaining a physician-investigator workforce. Key elements of this strategy are new programs to close gaps in the professional life cycle of physician-investigators, dedicated senior leaders collaborating with an experienced and diverse advisory committee, and a data-driven approach to programmatic evaluation. In this article, the implementation of integrated institutional programs including Institutional Mock Review for evaluation of grant proposals before submission, physician-scientist faculty mentoring, and effort matching programs are described. Detailed tactics are offered for tailoring these programs to a particular institution's background to maximize both efficiency and sustainability. The overarching strategy includes engaging multidisciplinary faculty as mentors and mentees, partnering with both clinical and basic science departments, integrating new programs with established approaches, and cultivating an emerging generation of physician-investigators as near-peer mentors and future leaders. This approach may serve as a useful paradigm for building an environment to nurture junior physician-investigators at other mid-sized academic institutions and may also have value for larger institutions in which there is fragmentation of the efforts to sustain the research careers of physicians.

Isolation and Identification of the Follicular Microbiome: Implications for Acne Research.

Our understanding of the microbiome and the role of Propionibacterium acnes in skin homeostasis and acne pathogenesis is evolving. Multiple methods for sampling and identifying the skin's microbiome exist, and understanding the differences between the abilities of various methods to characterize the microbial landscape is warranted. This study compared the microbial diversity of samples obtained from the cheeks of 20 volunteers, collected by surface swab, pore strips, and cyanoacrylate glue follicular biopsy, all sequenced with 16S rRNA sequencing (V1-V3) and whole-genome metagenomic sequencing. The sequencing method of choice influenced the detection of microbial profiles as whole-genome sequencing captured more species diversity, including viruses, compared with 16S sequencing. The relative abundance of bacterial or fungal species and overall diversity did not differ between sampling methods. However, the viral composition of the skin's surface is unique compared with the follicle, suggesting distinct viral niches within the skin. P. acnes bacteria, ribotypes, and bacteriophages were identified equally by all sampling methods indicating that the sampling method, whether for the skin's surface or follicle, does not impact P. acnes-related characterization and that all may be equally useful for acne-related research studies.

Practical management of acne for clinicians: An international consensus from the Global Alliance to Improve Outcomes in Acne.

Scientific advances are continually improving the knowledge of acne and contributing to the refinement of treatment options; it is important for clinicians to regularly update their practice patterns to reflect current standards. The Global Alliance to Improve Outcomes in Acne is an international group of dermatologists with an interest in acne research and education that has been meeting regularly since 2001. As a group, we have continuously evaluated the literature on acne. This supplement focuses on providing relevant clinical guidance to health care practitioners managing patients with acne, with an emphasis on areas where the evidence base may be sparse or need interpretation for daily practice.

Evidence-based recommendations for the management of acne fulminans and its variants.

BACKGROUND: Acne fulminans (AF) is a severe variant of inflammatory acne. It typically manifests as an explosive worsening and ulceration of skin lesions, and can be associated with systemic symptoms. However, there is a paucity of evidence-based information and no clear guidelines concerning the classification and treatment of AF. OBJECTIVE: To better define the spectrum of AF and its variants, devise optimal therapeutic approaches, and identify areas of future research. METHODS: A panel of physicians with expertise in severe acne vulgaris was convened after a comprehensive literature review of severe acne variants. Priority topics were reviewed and presented by each panelist at a 5-hour conference. Following review of the audiotape and scribed notes from the conference, surveys were utilized to address points of controversy and to clarify consensus recommendations. RESULTS: Appropriate clinical case presentations and consensus survey questions were utilized to create final recommendations based on both the literature and the expert consensus. LIMITATIONS: Limited evidenced-based data and prospective studies in the literature concerning the treatment of AF is available. CONCLUSION: These guidelines better characterize AF and provide health care practitioners approaches to the classification, treatment, and prevention of AF and its variants.

Inhibition of Sebum Production with the Acetyl Coenzyme A Carboxylase Inhibitor Olumacostat Glasaretil.

Olumacostat glasaretil (OG) is a small molecule inhibitor of acetyl coenzyme A (CoA) carboxylase (ACC), the enzyme that controls the first rate-limiting step in fatty acid biosynthesis. Inhibition of ACC activity in the sebaceous glands is designed to substantially affect sebum production, because over 80% of human sebum components contain fatty acids. OG inhibits de novo lipid synthesis in primary and transformed human sebocytes. TrueMass Sebum Panel analyses showed a reduction in saturated and monounsaturated fatty acyl chains across lipid species, including di- and triacylglycerols, phospholipids, cholesteryl esters, and wax esters in OG-treated sebocytes. There was no shift to shorter acyl chain lengths observed, suggesting that the fatty acid chain elongation process was not affected. OG is a pro-drug of the ACC inhibitor 5-(tetradecyloxy)-2-furoic acid and was designed to enhance delivery in vivo. Topical application of OG but not 5-(tetradecyloxy)-2-furoic acid significantly reduced hamster ear sebaceous gland size, indicating that this pro-drug approach was critical to obtain the desired activity in vivo. High-performance liquid chromatography analyses of hamster ear extracts showed that OG treatment increased ACC levels and the ratio of acetyl-CoA to free CoA in these animals, indicating increased fatty acid oxidation. These changes are consistent with ACC inhibition. Matrix-assisted laser desorption/ionization imaging showed that OG applied onto Yorkshire pig ears accumulated in sebaceous glands relative to the surrounding dermis. Sebaceous gland ACC represents an attractive therapeutic target given its central role in formation of sebum, a key factor in acne pathogenesis.

Efficacy, Safety, and Dermal Tolerability of Dapsone Gel, 7.5% in Patients with Moderate Acne Vulgaris: A Pooled Analysis of Two Phase 3 Trials.

Objective: Assess efficacy and safety of once-daily topical dapsone gel, 7.5% compared with vehicle for treating acne vulgaris (acne). Design: A pooled analysis of data from two identically designed, randomized, double-blind, vehicle-controlled, multicenter, 12-week clinical trials. Setting: Study sites in the United States and Canada. Participants: overall, 4,340 patients were randomized 1:1 to dapsone and vehicle. Criteria included age 12 years or older with acne diagnosis, 20 to 50 facial inflammatory lesions (papules and pustules), 30 to 100 facial noninflammatory lesions (open and closed comedones), and acne grade of 3 (moderate) on the Global Acne Assessment Score scale. Measurements: Efficacy assessments included the Global Acne Assessment Score success rate (proportion of patients with Global Acne Assessment Score of 0 [none] or 1 [minimal]) and percentage change from baseline in inflammatory and noninflammatory lesions at Week 12. Results: Global Acne Assessment Score success rates were 29.8 percent and 21.1 percent for patients who received dapsone gel, 7.5% and vehicle, respectively (p<0.001). Patients receiving dapsone gel, 7.5% had greater percentage change in lesion counts than patients receiving vehicle (inflammatory lesions: -54.6% vs. -48.1%; p<0.001; -45.1 %; noninflammatory lesions: -39.4%; p<0.001). Most adverse events were mild to moderate in severity. Mean dermal tolerability scores for stinging/burning, dryness, scaling, and erythema were similarly low with dapsone gel, 7.5% and vehicle. Conclusion: Dapsone gel, 7.5%, with a 50-percent greater dapsone concentration than twice-daily dapsone gel, 5% formulation, is applied topically once daily for acne, is effective, safe, and well-tolerated over 12 weeks, and has local tolerability similar to that of vehicle. www.clinicaltrials.gov identifiers: NCT01974141 and NCT01974323.

Consumption of dairy in teenagers with and without acne.

BACKGROUND: Recent literature has implicated dairy as having a potential acne-inducing effect. OBJECTIVES: The aim of this study was to investigate the link between dairy consumption and acne in teenagers. We tested the hypothesis that teenagers with facial acne consume more dairy than those without acne. METHODS: A case-control study was conducted among 225 participants, ages 14 to 19 years, with either moderate acne or no acne. Moderate acne was determined by a dermatologist using the Global Acne Assessment Scale. Participants who met inclusion criteria then completed up to three 24-hour diet recall interviews using the Nutrition Data System for Research software and food and nutrient intake were compared between groups. RESULTS: The amount of low-fat/skim milk consumed by participants with acne with significantly higher (P = .01) than those with no acne. No significant difference was found among total dairy intake, saturated fat or trans-fat, or glycemic load. No significant difference was found for total energy intake or body mass index. LIMITATIONS: Limitations include self-report of diet and portion size, and association does not determine causation. CONCLUSIONS: Consumption of low-fat/skim milk, but not full-fat milk, was positively associated with acne.

Standardized laboratory monitoring with use of isotretinoin in acne.

BACKGROUND: Laboratory monitoring for adverse effects to isotretinoin occurs with variability. Standardization of laboratory monitoring practices represents an opportunity to improve quality of care. OBJECTIVE: We sought to develop an evidence-based approach to laboratory monitoring of patients receiving isotretinoin therapy for acne. METHODS: We reviewed laboratory data from 515 patients with acne undergoing 574 courses of isotretinoin from March 2003 to July 2011. Frequency, timing, and severity of abnormalities were determined. RESULTS: Clinically insignificant leukopenia or thrombocytopenia occurred in 1.4% and 0.9% of patients, respectively. Elevated liver transaminases were detected infrequently and not significantly increased compared with baseline detection rates (1.9% vs 1.6% at baseline). Significant elevations occurred with triglyceride (19.3%) and cholesterol (22.8%) levels. The most severe abnormalities were grade 2 (moderate). Mean duration of treatment before abnormalities were detected was 56.3 days for hypertriglyceridemia, 61.9 days for alanine transaminitis, and 50.1 days for hypercholesterolemia. LIMITATIONS: This was a single-center experience examining variable isotretinoin laboratory monitoring practices. CONCLUSIONS: In healthy patients with normal baseline lipid panel and liver function test results, repeated studies should be performed after 2 months of isotretinoin therapy. If findings are normal, no further testing may be required. Routine complete blood cell count monitoring is not recommended.

Macrophage-tumor cell fusions from peripheral blood of melanoma patients.

BACKGROUND: While the morbidity and mortality from cancer are largely attributable to its metastatic dissemination, the integral features of the cascade are not well understood. The widely accepted hypothesis is that the primary tumor microenvironment induces the epithelial-to-mesenchymal transition in cancer cells, facilitating their escape into the bloodstream, possibly accompanied by cancer stem cells. An alternative theory for metastasis involves fusion of macrophages with tumor cells (MTFs). Here we culture and characterize apparent MTFs from blood of melanoma patients. METHODS: We isolated enriched CTC populations from peripheral blood samples from melanoma patients, and cultured them. We interrogated these cultured cells for characteristic BRAF mutations, and used confocal microscopy for immunophenotyping, motility, DNA content and chromatin texture analyses, and then conducted xenograft studies using nude mice. FINDINGS: Morphologically, the cultured MTFs were generally large with many pseudopod extensions and lamellipodia. Ultrastructurally, the cultured MTFs appeared to be macrophages. They were rich in mitochondria and lysosomes, as well as apparent melanosomes. The cultured MTF populations were all heterogeneous with regard to DNA content, containing aneuploid and/or high-ploidy cells, and they typically showed large sheets (and/or clumps) of cytoplasmic chromatin. This cytoplasmic DNA was found within heterogeneously-sized autophagic vacuoles, which prominently contained chromatin and micronuclei. Cultured MTFs uniformly expressed pan-macrophage markers (CD14, CD68) and macrophage markers indicative of M2 polarization (CD163, CD204, CD206). They also expressed melanocyte-specific markers (ALCAM, MLANA), epithelial biomarkers (KRT, EpCAM), as well as the pro-carcinogenic cytokine MIF along with functionally related stem cell markers (CXCR4, CD44). MTF cultures from individual patients (5 of 8) contained melanoma-specific BRAF activating mutations. Chromatin texture analysis of deconvoluted images showed condensed DNA (DAPI-intense) regions similar to focal regions described in stem cell fusions. MTFs were readily apparent in vivo in all human melanomas examined, often exhibiting even higher DNA content than the cultured MTFs. When cultured MTFs were transplanted subcutaneously in nude mice, they disseminated and produced metastatic lesions at distant sites. CONCLUSIONS AND HYPOTHESIS: Apparent MTFs are present in peripheral blood of patients with cutaneous melanomas, and they possess the ability to form metastatic lesions when transplanted into mice. We hypothesize that these MTFs arise at the periphery of primary tumors in vivo, that they readily enter the bloodstream and invade distant tissues, secreting cytokines (such as MIF) to prepare "niches" for colonization by metastasis initiating cells.

Activity-guided purification identifies lupeol, a pentacyclic triterpene, as a therapeutic agent multiple pathogenic factors of acne.

Acne vulgaris is a nearly universal cutaneous disease characterized by multifactorial pathogenic processes. Because current acne medications have various side effects, investigating new pharmacologically active molecules is important for treating acne. As natural products generally provide various classes of relatively safe compounds with medicinal potentials, we performed activity-guided purification after a series of screenings from the extracts of five medicinal plants to explore alternative acne medications. Lupeol, a pentacyclic triterpene, from the hexane extract of Solanum melongena L. (SM) was identified after instrumental analysis. Lupeol targeted most of the major pathogenic features of acne with desired physicochemical traits. It strongly suppressed lipogenesis by modulating the IGF-1R/phosphatidylinositide 3 kinase (PI3K)/Akt/sterol response element-binding protein-1 (SREBP-1) signaling pathway in SEB-1 sebocytes, and reduced inflammation by suppressing the NF-κB pathway in SEB-1 sebocytes and HaCaT keratinocytes. Lupeol exhibited a marginal effect on cell viability and may have modulated dyskeratosis of the epidermis. Subsequently, histopathological analysis of human patients' acne tissues after applying lupeol for 4 weeks demonstrated that lupeol markedly attenuated the levels of both the number of infiltrated cells and major pathogenic proteins examined in vitro around comedones or sebaceous glands, providing solid evidence for suggested therapeutic mechanisms. These results demonstrate the clinical feasibility of applying lupeol for the treatment of acne.

A retrospective analysis of the duration of oral antibiotic therapy for the treatment of acne among adolescents: investigating practice gaps and potential cost-savings.

BACKGROUND: Duration of oral antibiotic therapy in acne has not been widely studied. Recent guidelines suggest it should be limited to 3 to 6 months. OBJECTIVE: We sought to compare the duration of oral antibiotic use with recent guidelines and determine the potential cost-savings related to shortened durations. METHODS: This is a retrospective cohort study from the MarketScan Commercial Claims and Encounters database. Claims data were used to determine duration and costs of antibiotic therapy. RESULTS: The mean course duration was 129 days. The majority (93%) of courses were less than 9 months. Among the 31,634 courses, 18,280 (57.8%) did not include concomitant topical retinoid therapy. The mean (95% confidence interval) duration with and without topical retinoid use was 133 (131.5-134.7) days and 127 (125.4-127.9) days, respectively. The mean excess direct cost of antibiotic treatment for longer than 6 months was $580.99/person. LIMITATIONS: Claims cannot be attributed to a specific diagnosis or provider. The database does not provide information on acne severity. CONCLUSIONS: Duration of antibiotic use is decreasing when compared with previous data. However, 5547 (17.53%) courses exceeded 6 months, highlighting an opportunity for reduced antibiotic use. If courses greater than 6 months were shortened to 6 months, savings would be $580.99/person.