Reviewing the global burden of acne: how could we improve care to reduce the burden?

Acne (also known as acne vulgaris) remains the most common inflammatory dermatosis treated worldwide, as estimated by global skin disease prevalence studies. Latest reports suggest that the prevalence may be increasing in adolescents and adults, particularly female adults. The concept of 'burden of skin disease' is multidimensional and can be difficult to quantify in light of different healthcare systems across the globe. In acne, the resulting burden may vary according to patient demographics, access to treatments and duration of the disease. The visible nature of acne, symptoms and sequelae all contribute physically and psychosocially to the overall burden of disease, as do the costs required for management. Acne typically presents in adolescence at a time of significant transition. Profound effects on functional status have been demonstrated, along with a strong impact on interpersonal relationships, social functioning and mental health. The high prevalence of acne also presents an economic burden for society. The widespread and prolonged use of antibiotics introduces a potential added burden through resulting antimicrobial resistance. A James Lind Alliance Acne Priority Setting Partnership has identified numerous areas to inform future research, which would help to improve acne management and reduce the burden. The lack of standardized assessments is a major issue in acne trials and challenges the ability to compare treatments and perform meta-analyses. This paper reviews the current literature on burden of acne, identifies areas of treatment uncertainties and summarizes the work of the Acne Core Outcome Research Network as a means of supporting a reduction in the burden of disease.

Topical preparations for the treatment of mild-to-moderate acne vulgaris: systematic review and network meta-analysis.

BACKGROUND: Acne is very common and can have a substantial impact on wellbeing. Guidelines suggest first-line management with topical treatments, but there is little evidence regarding which treatments are most effective. OBJECTIVES: To identify the most effective and best tolerated topical treatments for acne using network meta-analysis. METHODS: CENTRAL, MEDLINE, Embase and World Health Organization Trials Registry were searched from inception to June 2020 for randomized trials that included participants with mild/moderate acne. Primary outcomes were self-reported improvement in acne, and trial withdrawal. Secondary outcomes included change in lesion counts, Investigator's Global Assessment, change in quality of life and total number of adverse events. Network meta-analysis was undertaken using a frequentist approach. Risk of bias was assessed using the Cochrane Risk of Bias Tool and confidence in evidence was assessed using CINeMA. RESULTS: A total of 81 papers were included, reporting 40 trials with a total of 18 089 participants. Patient Global Assessment of Improvement was reported in 11 trials. Based on the pooled network estimates, compared with vehicle, benzoyl peroxide (BPO) was effective (35% vs. 26%) for improving self-reported acne. The combinations of BPO with adapalene (54% vs. 35%) or with clindamycin (49% vs. 35%) were ranked more effective than BPO alone. The withdrawal of participants from the trial was reported in 35 trials. The number of patients withdrawing owing to adverse events was low for all treatments. Rates of withdrawal were slightly higher for BPO with adapalene (2·5%) or clindamycin (2·7%) than BPO (1·6%) or adapalene alone (1·0%). Overall confidence in the evidence was low. CONCLUSIONS: Adapalene in combination with BPO may be the most effective treatment for acne but with a slightly higher incidence of withdrawal than monotherapy. Inconsistent reporting of trial results precluded firmer conclusions.

MicroRNAs as biomarkers of atrophic scarring in acne: a cross-sectional analysis of 41 patients.

BACKGROUND: Acne is the commonest inflammatory dermatosis seen worldwide. Atrophic acne scarring is a frequent complication, which can arise from acne of any severity. Micro (mi)RNAs are noncoding RNA molecules of 19-25 nucleotides that function as post-transcriptomic mediators of gene expression. They have demonstrated differential expression in various pathologies, such as eczema and psoriasis, allowing for a unique miRNA 'signature' profile to be established for different disease states. AIM: To establish a miRNA signature for acne, and acne-associated atrophic scarring and to identify if a pattern of circulating miRNA is evident in patients who are prone to scarring. METHODS: In total, 41 participants were consecutively recruited to this study. Circulating miRNA was quantified from plasma samples in all 41 patients, while in 8 patients, and in a further validation cohort of 9 patients, whole miRNAome was undertaken from tissue specimens, which included lesional, normal and where present, scarred skin. RESULTS: Three miRNAs, miR-223, miR-21 and miR-150, were statistically significantly overexpressed in acne lesions, and notably, in clinically uninvolved skin in participants prone to scarring. In this subgroup, we also found statistically significantly elevated levels of circulating miRNA-21 and miRNA-150. CONCLUSION: The presence of elevated levels of these specific miRNAs in the serum of patients with acne raises the potential of a blood test to identify those at risk of scarring, allowing for earlier intervention with effective therapy.

Is Cutibacterium (previously Propionibacterium) acnes a potential pathogenic factor in the aetiology of the skin disease progressive macular hypomelanosis?

Progressive macular hypomelanosis (PMH) is a skin condition that normally causes symmetrically distributed hypopigmented macules on the front and back of the trunk, but rarely the face. To date, the pathophysiology of the condition is not well understood, but a role for the anaerobic skin bacterium Cutibacterium (previously Propionibacterium) acnes in the development of the disease has been proposed due to its sole presence within lesional, but not normal peri-lesional, skin. The success of antimicrobials in the treatment of PMH also provides circumstantial evidence that this association may be causal, although this is still to be proven. More recent culture and metagenomic typing studies indicate that strains of C. acnes subsp. elongatum (type III) may be important in the aetiology of the condition, which would help to explain why PMH does not normally affect the face since such strains are rarely present there, and why no association between this condition and acne vulgaris is found; acne appears to primarily involve type IA1 strains from C. acnes subsp. acnes (type I). In this review, we summarize current knowledge on the relationship between C. acnes and PMH, and re-examine previous challenges to the view that the bacterium plays a role in the condition against the backdrop of newly emerged data.

Assessing effectiveness in acne clinical trials: steps towards a core outcome measure set.

BACKGROUND: Acne ranks second to dermatitis in terms of global burden of skin disease. As such, it is essential that data on treatment efficacy are generated in a way that maximizes the opportunity for comparison among treatments. Interest in developing core outcome sets for use in clinical trials to standardize data collection in skin disease is surging. OBJECTIVES: The goal of this review is to provide an update on the efforts underway, challenges encountered and future directions in the development of an acne core outcome measure set for use in clinical trials. METHODS: The activities of the Acne Core Outcomes Research Network (ACORN) are presented in the context of currently acceptable methodologies for core outcome set development. CONCLUSIONS: Emphasis is placed on following a rigorous methodology, involving patients and recognizing a role for emerging technologies.

Light therapies for acne: abridged Cochrane systematic review including GRADE assessments.

We undertook a Cochrane review of randomized controlled trials (RCTs) evaluating the effects of light-based interventions for acne vulgaris. We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science and grey literature sources (September 2015). We used the Grading of Recommendations Assessment, Development and Evaluation Working Group approach to assess the quality of evidence (QoE). We included 71 RCTs (4211 participants, median sample size 31). Results from a single study (n = 266, low QoE) showed little or no difference in effectiveness on participants' assessment of improvement between 20% aminolaevulinic acid (ALA) photodynamic therapy (PDT), activated by blue light, vs. vehicle plus blue light, whereas another study (n = 180) comparing ALA-PDT (red light) concentrations showed that 20% ALA-PDT was no more effective than 15% ALA-PDT but better than 10% and 5% ALA-PDT. Pooled data from three studies (n = 360, moderate QoE) showed that methyl aminolaevulinate PDT, activated by red light, had a similar effect on changes in lesion counts vs. placebo cream with red light. Several studies compared yellow light with placebo or no treatment, infrared light with no treatment, gold microparticle suspension with vehicle and clindamycin/benzoyl peroxide (C/BPO) combined with pulsed dye laser with C/BPO alone. None of these showed any clinically significant effects. Most studies reported adverse effects, but inadequately, with scarring reported as absent, and blistering only in studies on intense pulsed light, infrared light and PDT (very low QoE). Carefully planned studies, using standardized outcome measures and common acne treatments as comparators, are needed.

Interventional management of hyperhidrosis in secondary care: a systematic review.

BACKGROUND: Hyperhidrosis is uncontrollable excessive sweating, which occurs at rest, regardless of temperature. The symptoms of hyperhidrosis can significantly affect quality of life. OBJECTIVES: To undertake a systematic review of the clinical effectiveness and safety of treatments available in secondary care for the management of primary hyperhidrosis. METHODS: Fifteen databases (including trial registers) were searched to July 2016 to identify studies of secondary-care treatments for primary hyperhidrosis. For each intervention randomized controlled trials (RCTs) were included where available; where RCT evidence was lacking, nonrandomized trials or large prospective case series were included. Outcomes of interest included disease severity, sweat rate, quality of life, patient satisfaction and adverse events. Trial quality was assessed using a modified version of the Cochrane Risk of Bias tool. Results were pooled in pairwise meta-analyses where appropriate, otherwise a narrative synthesis was presented. RESULTS: Fifty studies were included in the review: 32 RCTs, 17 nonrandomized trials and one case series. The studies varied in terms of population, intervention and methods of outcome assessment. Most studies were small, at high risk of bias and poorly reported. The interventions assessed were iontophoresis, botulinum toxin (BTX) injections, anticholinergic medications, curettage and newer energy-based technologies that damage the sweat gland. CONCLUSIONS: The evidence for the effectiveness and safety of treatments for primary hyperhidrosis is limited overall, and few firm conclusions can be drawn. However, there is moderate-quality evidence to support the use of BTX for axillary hyperhidrosis. A trial comparing BTX with iontophoresis for palmar hyperhidrosis is warranted.

Validation of 3D skin imaging for objective repeatable quantification of severity of atrophic acne scarring.

BACKGROUND: One major sequelae of acne is atrophic scarring, yet objective tools to assess scars are lacking. Neither depth nor volume of atrophic scars is readily evaluable clinically and standard 2D photography is significantly affected by lighting and shadows. The aim of our study was to define and evaluate parameters of 3D imaging that can be used to assess severity of atrophic acne scarring. METHODS: Single center study of 31 patients with acne scarring. A target area of 3 × 3 cm was defined on the face. The global severity of atrophic acne scarring in the target area was evaluated by 5 dermatologists and scars were counted and categorized by size (scars < 2 mm, 2-4 mm, and > 4 mm in diameter). Three dimensional images of the target area were acquired with the LifeViz Micro® system and analysis was performed using MountainsMaps® software. An algorithm was developed to quantify the scar volume loss: shape removal step, with an order 5 polynomial, and to calculate the Valley void volume 80% (Vvv 80%) defined in the ISO-25178 standard for 3D surface texture. RESULTS: Correlation coefficient of the Vvv parameter to mean global severity at the target area rating was 0.77. The volume of scars evaluated with the Vvv parameter was mainly impacted by scars > 2 mm. The evaluations demonstrated good repeatability (with an intra-class correlation coefficient ICC = 0.98). CONCLUSIONS: We demonstrate convergent validation to clinical assessment and repeatability of 3D skin imaging in atrophic acne scarring. Image analysis is straightforward and can be integrated into an automated workflow.

AGREE II assessments of recent acne treatment guidelines: how well do they reveal trustworthiness as defined by the U.S. Institute of Medicine criteria?

BACKGROUND: Up-to-date, trustworthy guidelines are a widely relied upon means of promoting excellent patient care. OBJECTIVES: To determine the quality of recently published acne treatment guidelines by utilizing the Appraisal of Guidelines for Research and Evaluation (AGREE) II Reporting Checklist, the U.S. Institute of Medicine's (IOM) criteria of trustworthiness, the red flags of Lenzer et al. and CheckUp. METHODS: Systematic searches were conducted in bibliographic databases, guideline depositories and using Google to identify acne treatment guidelines published since 2013. Six assessors independently scored each guideline using the AGREE II Reporting Checklist. Guidelines were concomitantly assessed for trustworthiness using the IOM criteria and for the red flags of Lenzer et al., indicative of potential bias. Updates were screened using CheckUp. RESULTS: Eight guidelines were identified, two of which were updates. Lowest scoring AGREE II domains across all guidelines were applicability (six poor, one fair, one average) and rigour (four poor, one fair, three average). Two of the three highest-scoring guidelines were developed using AGREE II. No guideline fully met each IOM criterion and all raised at least one red flag indicative of potential bias. One updated guideline did not address seven of 16 items on CheckUp and the other did not address four. Patient involvement in guideline development was minimal. CONCLUSIONS: Use of the AGREE II instrument during guideline development did not have as great an effect on guideline quality as might be expected. There is considerable room for improvement in acne treatment guidelines in order to satisfy the IOM trustworthiness criteria and avoid bias.

The management of acne vulgaris in primary care: a cohort study of consulting and prescribing patterns using the Clinical Practice Research Datalink.

BACKGROUND: Effective management of acne vulgaris in primary care involves support (usually provided over a number of consultations) and prescription of effective treatments. However, consulting and prescribing patterns for acne in primary care are not well described. OBJECTIVES: To describe the rate of primary-care consultations and follow-up consultations; prescribing patterns, including overall use of acne-related medications (ARMs); and initial and follow-up prescription for acne vulgaris in the U.K. METHODS: U.K. primary-care acne consultations and prescriptions for ARMs were identified in the Clinical Practice Research Datalink. Annual consultation rates (between 2004 and 2013) by age and sex, new consultations and consultations in the subsequent year were calculated, along with prescribing trends - during a new consultation and over the subsequent 90 days and year - using the number of registered patients as the denominator. RESULTS: Two-thirds (66·1%) of patients who had a new acne consultation had no further acne consultations in the subsequent year. Overall 26·7%, 24·9%, and 23·6% and 2·8% of patients were prescribed no ARM, an oral antibiotic, a topical antibiotic or an oral plus topical antibiotic, respectively, during a new acne consultation. In total 60·1% and 38·6% of patients prescribed an ARM received no further ARM prescriptions in the following 90 days and 1 year, respectively, despite most prescriptions being for 2 months or less. Prescribing rates for lymecycline and topical combined clindamycin and benzoyl peroxide increased substantially between 2004 and 2013. There were no important changes in consultation rates between 2004 and 2013. CONCLUSIONS: These data suggest that patients with acne are receiving a suboptimal initial choice of ARMs, longitudinal care and prescribing.

Large-scale international study enhances understanding of an emerging acne population: adult females.

BACKGROUND: Acne vulgaris is increasingly recognized in adult women; however, few studies have formally evaluated the clinical presentation and factors associated with acne in this population. METHODS: This prospective, observational international study evaluated the clinical characteristics and lifestyle correlates of acne in adults (≥25 years) at a dermatology visit for acne. Investigators conducted a detailed clinical examination and administered a validated questionnaire that covered medical history, disease evolution, lifestyle habits, previous treatments, skin care and quality of life. RESULTS: In this study (n = 374), acne was mild or clear/almost clear in 47.3% of subjects; however, the study visit was not required to be an initial consultation for acne and as such, many patients were already on treatment. Most women (89.8%) had acne involving multiple facial zones (cheeks, forehead, mandibular area, temples) with a spectrum of facial acne severity similar to adolescents. Mixed facial acne (both inflammatory and non-inflammatory lesions present) was the most common presentation; 6.4% of women had inflammatory acne only (no non-inflammatory lesions reported) and 17.1% had comedonal acne with no inflammatory lesions. Truncal acne was present in 48.4% of patients. A small subset (11.2%) had acne localized only to the mandibular area. Compared to the women without localized acne, those with mandibular acne were more likely to be employed (90.5% vs. 78.6%), reported greater daily stress levels (5.8 vs. 5.1), and were more likely to say their jobs were psychologically stressful (71.4% vs. 57.5%). Women with mandibular acne alone were significantly less likely to have a global acne severity rating of moderate or higher (7.1% vs. 50.1%), truncal acne (19.0% vs. 51.9%), post-inflammatory hyperpigmentation (23.8% vs. 51.9%) and erythema (19.0% vs. 48.4%). At the completion of the study visit, this group was also more likely to receive a prescription for an anti-androgen (16.7% vs. 7.7%). CONCLUSIONS: This study represents the first objective assessment of the facial distribution of acne lesions in adult women presenting to the dermatology office. The data surprisingly indicate that the acne distribution in almost 90% of cases is similar to that seen in adolescent acne. The stereotype of adult female acne being due to hormonal disturbances presenting as inflammatory acne localized only to the mandibular area was not found in the majority of this large group. The large majority (93.7%) of women had facial comedones. We recommend that the general treatment approach for adult acne should include agents that target each of the acne lesion subtypes. Subgroup analyses of recent large-scale controlled clinical trials have shown that many adult women respond well to standard first-line acne therapy.

Brimonidine gel 0.33% rapidly improves patient-reported outcomes by controlling facial erythema of rosacea: a randomized, double-blind, vehicle-controlled study.

BACKGROUND: Facial redness contributes to impaired psychosocial functioning in rosacea patients and the only approved treatment for erythema is topical brimonidine gel 0.33%. OBJECTIVES: To evaluate patient-reported outcomes, as well as efficacy and safety, in subjects with self-perceived severe erythema treated with brimonidine gel 0.33% compared to vehicle. METHODS: An 8-day multicenter, randomized study comparing once-daily brimonidine gel 0.33% with vehicle gel using a facial redness questionnaire, subject satisfaction questionnaire and a patient diary of facial redness control to assess patient-reported outcomes. RESULTS: Of the 92 included subjects with self-perceived severe erythema, very few were satisfied with their appearance at baseline (4.2% brimonidine group, 0 vehicle group). On Day 8, significantly more brimonidine group subjects were satisfied with their facial appearance compared to vehicle group (36.9% vs. 21.5%; P < 0.05), with the overall treatment effect (69.6% vs. 40.4%; P < 0.01), and with the improvement in their facial redness (67.4% vs. 33.3%; P < 0.001). More brimonidine group subjects were able to control their facial redness daily (e.g. 83.0% vs. 38.9% on Day 1). On Day 8, significantly more brimonidine group subjects than vehicle group had at least a one-grade improvement from baseline in the Clinician Erythema Assessment score (71.7% vs. 35.7%; P = 0.0011) and Patient Self-Assessment score (76.1% vs. 47.6%; P = 0.004). More subjects in the brimonidine group (29.2%) reported treatment-related adverse events than in the vehicle group (15.9%) but most were mild and transient. CONCLUSIONS: Once-daily brimonidine gel 0.33% allowed patients to rapidly control their facial redness and significantly improved patient-reported outcomes in the treatment of persistent facial erythema of rosacea.

Interleukin-10 secretion from CD14+ peripheral blood mononuclear cells is downregulated in patients with acne vulgaris.

BACKGROUND: Acne is a common chronic inflammatory dermatosis of the pilosebaceous unit. It is characterized by seborrhoea, comedone formation and an inflammatory response consistent with defective cellular immunity to Propionibacterium acnes. OBJECTIVES: The objective of this study was to investigate the immune reactivity of patients with acne compared with healthy controls by examining the response of peripheral blood mononuclear cells (PBMCs) to stimulation with P. acnes. Particular focus was placed upon measuring the production of interleukin (IL)-10, which has an established immunoregulatory role. PATIENTS AND METHODS: Venous blood was collected from 47 patients with acne and 40 age- and sex-matched healthy controls with no prior history of acne. PBMCs were cultured and their cytokine response to P. acnes investigated. RESULTS: Proinflammatory IL-8 and tumour necrosis factor (TNF)-alpha secretion from PBMCs was higher in patients with acne when stimulated with P. acnes. In contrast, a statistically significant reduction in PBMC secretion of anti-inflammatory IL-10 in patients with acne was identified. The impaired production of IL-10 by PBMCs from patients with acne was confined to CD14+ cells presumed to be monocytes. The ability of CD14 cells from patients with acne to phagocytose P. acnes bacteria was also observed to be defective but the addition of exogenous IL-10 to PBMC cultures restored phagocytic activity. CONCLUSIONS: These data suggest that patients with acne have a proinflammatory cytokine milieu and crucially are unable to contain early inflammatory changes due to a specific defect in immunosurveillance, namely low monocyte IL-10 production. Our observations raise the possibility that acne therapeutics might profitably target IL-10 both as a regulator of proinflammatory cytokines and in augmenting the CD14+ cell phagocytic response.

Cutaneous infection with an Alternaria sp. in an immunocompetent host.

We report a case of cutaneous alternariosis in an immunocompetent 85-year-old man. Identification of the causative organism in this patient was achieved by 18S rRNA sequencing. A 6-month course of itraconazole led to a good clinical response.