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.

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.

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.

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.

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.

Transcriptomic Analyses Predict Enhanced Metabolic Activity and Therapeutic Potential of mTOR Inhibitors in Acne-Prone Skin.

Current acne therapies center on preventing new lesions in patients with acne. These therapies were historically found to be beneficial yet were chosen without knowledge of the specific changes in the skin that favor lesion development. A major challenge in developing new treatments is the incomplete understanding of nonlesional (NL), acne-prone skin's molecular characteristics. To address this, we compared RNA-sequencing data from NL skin of 49 patients with acne (denoted as NL acne [NLA]) with those from 19 healthy controls with no acne history. We found 77 differentially expressed genes in NLA (log fold change > 1; P < .05), including genes associated with innate immunity and epidermal barrier function. Notably, K RT 6C, K RT 16, S100A8, S100A9, and lactotransferrin were upregulated, and LCE4A, LCE6A, and CTSE were downregulated. Gene set enrichment analysis revealed that metabolic pathways were enriched in NLA skin, whereas keratinization was negatively enriched. To identify compounds that could shift the gene expression signature of NLA skin toward healthy control skin, we performed connectivity mapping with the Library of Integrated Network-Based Signatures. We identified 187 compounds, particularly mTOR inhibitors, that could potentially normalize the gene expression profile of acne-prone skin to that of healthy skin. Our findings indicate that NLA skin has distinct differences in epidermal differentiation, cellular metabolism, and innate immunity that may promote lesion formation and suggest that mTOR inhibitors could restore NLA skin toward a healthier state, potentially reversing the predisposition to lesion development.

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.

Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells.

13-cis retinoic acid (13-cis RA; also known as isotretinoin) is the most potent agent available for treatment of acne. It is known that the drug induces apoptosis in cells cultured from human sebaceous glands, but its mechanism of action has not been determined. In this study, skin biopsies were taken from 7 patients with acne prior to and at 1 week of treatment with 13-cis RA. TUNEL staining confirmed that 13-cis RA induced apoptosis in sebaceous glands. Transcriptional profiling of patient skin and cultured human sebaceous gland cells (SEB-1 sebocytes) indicated that lipocalin 2 was among the genes most highly upregulated by 13-cis RA. Lipocalin 2 encodes neutrophil gelatinase-associated lipocalin (NGAL), which functions in innate immune defense and induces apoptosis of murine B lymphocytes. Increased immunolocalization of NGAL was noted in patients' sebaceous glands following treatment with 13-cis RA, and recombinant NGAL induced apoptosis in SEB-1 sebocytes. Furthermore, apoptosis in response to 13-cis RA was inhibited in the presence of siRNA to lipocalin 2. These data indicate that NGAL mediates the apoptotic effect of 13-cis RA and suggest that agents that selectively induce NGAL expression in sebaceous glands might represent therapeutic alternatives to the use of 13-cis RA to treat individuals with 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.

Impact of a fixed combination of clindamycin phosphate 1.2%-benzoyl peroxide 2.5% aqueous gel on health-related quality of life in moderate to severe acne vulgaris.

The acne-specific quality of life (Acne-QoL) questionnaire was developed to measure the impact of facial acne across 4 domains (acne symptoms, role-emotional, self-perception, role-social) of health-related quality of life (HRQL). This analysis assessed the impact of clindamycin phosphate 1.2%-benzoyl peroxide 2.5% (clindamycin-BPO 2.5%) gel on HRQL in a combined study population (N = 2813) of participants with moderate to severe acne vulgaris. Although the results presented within do not include factors of study and study-by-treatment interaction, analyses were performed to confirm that the results were consistent across the 2 identical, double-blind, randomized studies and within each treatment group across studies to justify pooling the data from both studies. The Acne-QoL questionnaire was administered at baseline and at the end of treatment (week 12). Treatment with clindamycin-BPO 2.5% gel significantly improved participant-reported HRQL across all 4 domains compared with individual active ingredients and vehicle (P < .001). The percentage improvement in mean Acne-QoL domain scores with clindamycin-BPO 2.5% gel ranged from 37% to 59%. Because the negative impact of facial acne on HRQL is one of the primary motivators for patients to seek treatment, this analysis underscores the importance of physicians incorporating assessments of HRQL into their clinical decision making.

A multicenter study of topical azelaic acid 15% gel in combination with oral doxycycline as initial therapy and azelaic acid 15% gel as maintenance monotherapy.

This two-phase, multicenter study was undertaken to examine the safety and efficacy of combination therapy with oral doxycycline and topical azelaic acid (AzA) 15% gel in moderate-to-severe papulopustular rosacea and to determine the effect of subsequent maintenance monotherapy with AzA 15% gel alone. In the initial open-label, non-randomized phase of the study, subjects (n=172) received topical AzA 15% gel and oral doxycycline (100 mg), both twice daily, for < or = 12 weeks. In the second, double-blind study phase, subjects who had initially undergone at least four weeks of combination treatment in phase 1 and who achieved > or = 75% inflammatory lesion count reduction (n=136) were randomized to receive either AzA 15% gel or its vehicle twice daily for an additional 24 weeks. Assessments of efficacy were obtained at four-week intervals throughout both phases of the study and included change in inflammatory lesion count, investigator global assessment (IGA) of rosacea severity, and separate assessments of erythema and telangiectasia severity. At the last visit for each phase of the study, the investigator and participant each rated overall improvement, with the participant rating cosmetic acceptability and the investigator rating treatment as "success" or "failure" based on IGA score. During the second phase of the trial, the rate of relapse -- defined as either a 50% deterioration in the lesion count improvement from phase 1, an increase in erythema intolerable to the subject or maintenance therapy failure as judged by the investigator and/or the subject -- was obtained. Safety assessments were conducted for both phases of the study and included analysis of adverse events (AEs) and a rating of cutaneous tolerability by the subject. By week 12 of the open-label phase of the study, 81.4% of subjects had reached a 75% or greater reduction in inflammatory lesion count, and 64% of patients achieved treatment success. During the second study phase (maintenance phase), AzA 15% gel consistently provided a better maintenance response than vehicle, with maintenance of remission in 75% of patients over the six-month duration of the maintenance phase. Additionally AzA 15% gel showed a statistically significantly lower deterioration in absolute inflammatory lesion counts than did vehicle after 8, 16, 20 and 24 weeks of maintenance therapy. No serious treatment-related AEs were encountered in the study, and 98.5% of subjects were satisfied with the local tolerability of both AzA gel and vehicle.

Changing the face of acne therapy.

Many innovations in acne therapy have evolved since the discovery in 1949 that vitamin A derivatives affected epidermal proliferation. Approval of topical tretinoin solution in 1971 was followed by modifications in the formulation to improve tolerability and provide flexibility in dosing. Identification of retinoid receptors led to research that resulted in 2 receptor-selective synthetic retinoids: adapalene and tazarotene. Today, topical retinoids are one of the cornerstones of acne therapy and are recommended as first-line therapy for all but the most severe forms of acne. They are used as monotherapy in mild comedonal acne; for inflammatory acne, topical retinoids are used in combination with benzoyl peroxide (BPO) and antibiotics (topical or oral) and/or hormonal therapy for females. Because of the high prevalence of antibiotic-resistant strains of Propionibacterium acnes, topical antibiotics should no longer be used as monotherapy. Topical retinoid monotherapy is recommended for maintenance because it prevents formation of microcomedones, the precursor lesions in acne. Combination topical retinoid/antimicrobial therapy has become the current recommended standard of care for the management of patients with acne. Combination therapy can target multiple pathogenic factors: abnormal follicular keratinization, P acnes proliferation, inflammation, and increased sebum production. A number of fixed-combination products are available. These products are effective, generally well-tolerated, and more convenient for patients than multiple individual agents. By reducing the number of medications and applications, fixed-combination products have the potential to improve patient adherence, thereby improving treatment outcomes.

Long-term safety and efficacy study of adapalene 0.3% gel.

The efficacy and safety of adapalene 0.1% gel in the treatment of acne vulgaris has been demonstrated in multiple controlled clinical trials. A higher concentration formulation, adapalene 0.3% gel, has been developed to provide a broader range of treatment options for acne management. Phase 3 clinical studies have demonstrated the superior efficacy of adapalene 0.3% gel compared to adapalene 0.1% gel and its vehicle at the end of a 12-week treatment period. The goal of this study was to evaluate the long-term safety of adapalene 0.3% gel in subjects treated once daily for 52 weeks, with a secondary objective to evaluate long-term efficacy. Subjects 12 years of age or older (N=551) with acne vulgaris participated in a multicenter, open-label study of the long-term (up to 52 weeks) efficacy and safety of once-daily applications of adapalene 0.3% gel. Of those enrolled, 167 subjects completed 12 months of treatment. Expected signs and symptoms of local cutaneous irritation (erythema, dryness, scaling, and stinging/burning) were mostly mild or moderate, with mean tolerability scores below 1 (mild) at all time points for the parameters assessed. Treatment-related, dermatologic adverse events were experienced by 21% of subjects and dry skin, skin discomfort, and scaling were reported by 10.5%, 8.3% and 3.3% of subjects, respectively. Most of the adverse events reported occurred in the first quarter of treatment. Adverse events were mostly mild to moderate in severity. Subjects treated with adapalene 0.3% gel for 52 weeks achieved a >75% median reduction in total, inflammatory, and noninflammatory lesions in this open-label study by the end of the treatment period. Adapalene 0.3% gel was safe and effective in the long-term (up to 1 year) treatment of subjects with acne vulgaris.

Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea.

BACKGROUND: Twice-daily azelaic acid (AzA) is the conventional regimen for papulopustular rosacea, but once-daily AzA may be equally effective, with greater convenience and dosing flexibility. In order to test this hypothesis, an exploratory study was conducted. METHODS: The evaluable efficacy population of this 12-week double-blind, parallel-group study included 72 patients and the population that was used to report safety results included 92 patients. Baseline characteristics were comparable between the once-daily and twice-daily study groups. Evaluations were performed at baseline and at weeks 4, 8, and 12. RESULTS: No significant difference was found between the once-daily and twice-daily groups at the end of study therapy in mean investigator global assessment (IGA) scores, treatment success, or treatment response. The mean number of inflammatory lesions, the intensity of erythema intensity, and the intensity of telangiectasia at treatment end were likewise not significantly different (P>.205 for all). More than 90% of subjects in each group rated cosmetic acceptability of this AzA gel as satisfactory or better. CONCLUSION: Based on these findings and those of prior studies, once-daily AzA 15% gel can therefore be utilized as a safe, effective, and economical dosing option for the treatment of mild-to-moderate papulopustular rosacea. Once-daily dosing of AzA 15% gel was well accepted by patients and can offer considerable dosing flexibility and convenience for the patient as well as for the dermatologist.

Overview of acne and its treatment.

Acne affects more than 85% of teenagers in the United States and often continues into adulthood. The most deleterious form can result in permanent scarring on the face, chest, and back. Although the pathogenic features of acne are well known, the initiating factor remains unknown. Isotretinoin is effective against all of the pathogenic features of acne but is contraindicated in pregnant women and has been associated with elevations in triglyceride levels. Combination regimens appear to be effective, but physicians should avoid prescribing complicated treatment regimens. Hormone therapy has been found to improve acne in some women and should be considered in appropriate candidates. Although the list of available and effective agents appears to be extensive, several are contraindicated in pregnant women, and long-term use of antibiotics to target inflammation has been linked to agranulocytosis and Stevens-Johnson syndrome. Further investigation into agents that can reduce sebum production is warranted.

Improving outcomes through collaboration.

A roundtable was convened to examine the issues surrounding the use of hormonal therapy in the treatment of acne. Obstetrician-gynecologists (OB/ GYNs) and dermatologists often have varying views with regard to the use of oral contraceptives (OCs) and other agents in patients with acne. If polycystic ovary syndrome (PCOS), the most common hormonal cause of acne, has been diagnosed, the use of OCs is not usually disputed. Hormonal evaluation is recommended for certain conditions such as virilization. Although PCOS is often the source of the problem, it is important to rule out a testosterone-producing tumor or an adrenal tumor. It was determined, however, that the perception that OCs cause cervical and breast cancer persists among some dermatologists. Even in women with a family history of breast cancer, OCs do not increase the risk. Nor is cervical cancer related to OC use; rather, it results from human papillomavirus. Thus, patients should be assured that OCs will not increase their risk for either of these cancers. Female patients should be advised to see their gynecologists annually for breast and pelvic examinations and to discuss their concerns surrounding the use of OCs.