Acne treatments: future trajectories.

Current acne treatments present several limitations, posing the need for new effective therapies for long-term administration for recalcitrant or relapsing acne. Key players in acne that may emerge as targets for future acne treatments include the cutaneous loss of diversity of Cutibacterium (formerly Propionibacterium) acnes phylotypes and the insulin-like growth factor-1 signalling pathway. New data about the loss of diversity of microbiota in acne provides the rationale for the potential use of oral or topical probiotics. Another therapeutic approach to modulate the microbiota could be topical formulation of C. acnes bacteriophages to target specifically the pathogenic 'acnegenic' C. acnes phylotypes. Insulin-sensitizing agents such as metformin, myo-inositol and d-chiro-inositol represent promising agents, but to date there have been only limited studies and much heterogeneity in the methods of assessing acne efficacy outcomes. Moving towards a holistic approach for patients with acne is the future, by taking into account both internal and external factors, such as pollution, stress, acne family history, age, smoking habits and diet, and addressing quality of life and the psychological impact of acne.

Actualités sur la prise en charge des kératoses actiniques chez les patients transplantés d'organes: Management of actinic keratoses in organ transplant recipients: an update.

Transplant recipients are at high risk of developing actinic keratosis (AK) and skin cancer. For this reason, initiating treatment at an early stage is crucial. Topical and systemic therapeutic options for AK have widely been described in studies of immunocompetent patients. However, little is known about AK management in organ transplant recipients (OTR). Photodynamic therapy (PDT), along with imiquimod, topical NSAIDs and topical 5-fluorouracil have been used on ORT patients in small non randomized studies. Although these studies seem to suggest that PDT offers best results, solid evidence is lacking. Nicotinamide and oral retinoids have also been described as reasonably effective preventive treatments in ORT patients. Management of immunosuppressive drugs is also considered as a key point for reducing the number of AK in ORT patients; an early switch for m-tor inhibitors has been shown to be protective while azathioprine, ciclosporin and tacrolimus have been shown to heighten the risk of developing AKs and skin cancer in this population. © 2019 Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Kératoses actiniques : comprendre et traiter réalisé avec le soutien institutionnel de Galderma International.

Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-γ agonist trifarotene.

BACKGROUND: 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. OBJECTIVES: To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. MATERIALS AND METHODS: In vitro assays determined efficacy, potency and selectivity on RARs, as well as the activity on the expression of retinoid target genes in human keratinocytes and ex vivo cultured skin. In vivo studies investigated topical comedolytic, anti-inflammatory and depigmenting properties. The trifarotene-induced gene expression profile was investigated in nonlesional skin of patients with acne and compared with ex vivo and in vivo models. Finally, the metabolic stability in human keratinocytes and hepatic microsomes was established. RESULTS: Trifarotene is a selective RARγ agonist with > 20-fold selectivity over RARα and RARß. 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 anti-inflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, retinoic acid metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after 4 weeks of topical application of trifarotene 0·005% cream. CONCLUSIONS: Based on its RARγ 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 favourable safety profile in acne and ichthyotic disorders.

Characterisation of Cutibacterium acnes phylotypes in acne and in vivo exploratory evaluation of Myrtacine®.

OBJECTIVE: Our main objective was to compare Cutibacterium acnes (C. acnes) skin colonisation in patients with mild to moderate acne versus healthy controls and secondly, to evaluate a Myrtacine® -based cream on C. acnes total population and antibioresistant Cutibacteria in patients with acne. METHODS: In 60 acne patients (Global Acne Severity Scale, GEA grades 2-3), of mean age 20 [15-30] years and in 24 age- and sex- matched healthy controls, forehead strips samplings were performed for microbiological analysis of comedones by colony forming unit (CFU) counts of global C. acnes and erythromycin (EryR) or clindamycin-resistant (ClnR) populations of Cutibacterium and determination of phylotypes by MALTI-TOF. Clinical evaluations of acne patients (GEA, lesion count, porphyrin fluorescence) were performed at baseline and after 56 days of twice-daily application of a Myrtacine® -based cream. RESULTS: We first showed (i) high and similar levels of C. acnes colonisation in superficial pilosebaceous follicles and detection of EryR and ClnR strains in both acne and control groups; (ii) different repartition of phylotypes in acne patients versus healthy control, with a predominance of phylotype IA in acne patients and a link between phylotype IA and erythromycin resistance. Besides, after treatment with the Myrtacine® -based cream in acne patients, there was no change in C. acnes total load, but a significant decrease of EryR Cutibacteria, reduced porphyrin production by C. acnes, a decrease in acne severity (GEA), associated with reduced retentional and inflammatory lesions. CONCLUSION: Cutibacterium acnes colonisation was not significantly different in acne versus control groups. Phylotype IA was predominant in acne patient and in EryR C. acnes. A Myrtacine® -based cream significantly reduced the level of EryR Cutibacteria in vivo and improved acne lesions.

A consensus-based practical and daily guide for the treatment of acne patients.

BACKGROUND: Many current guidelines provide detailed evidence-based recommendations for acne treatment. OBJECTIVE: To create consensus-based, simple, easy-to-use algorithms for clinical acne treatment in daily office-based practice and to provide checklists to assist in determining why a patient may not have responded to treatment and what action to take. METHODS: Existing treatment guidelines and consensus papers were reviewed. The information in them was extracted and simplified according to daily clinical practice needs using a consensus-based approach and based on the authors' clinical expertise. RESULTS: As outcomes, separate simple algorithms are presented for the treatment of predominant comedonal, predominant papulopustular and nodular/conglobate acne. Patients with predominant comedonal acne should initially be treated with a topical retinoid, azelaic acid or salicylic acid. Fixed combination topicals are recommended for patients with predominant papulopustular acne with treatment tailored according to the severity of disease. Treatment recommendations for nodular/conglobate acne include oral isotretinoin or fixed combinations plus oral antibiotics in men, and these options may be supplemented with oral anti-androgenic hormonal therapy in women. Further decisions regarding treatment responses should be evaluated 8 weeks after treatment initiation in patients with predominant comedonal or papulopustular acne and 12 weeks after in those with nodular/conglobate acne. Maintenance therapy with a topical retinoid or azelaic acid should be commenced once a patient is clear or almost clear of their acne to prevent the disease from recurring. The principal explanations for lack of treatment response fall into 5 main categories: disease progression, non-drug-related reasons, drug-related reasons, poor adherence, and adverse events. CONCLUSION: This practical guide provides dermatologists with treatment algorithms adapted to different clinical features of acne which are simple and easy to use in daily clinical practice. The checklists to establish the causes for a lack of treatment response and subsequent action to take will facilitate successful acne management.

Verneuil's disease, innate immunity and vitamin D: a pilot study.

BACKGROUND: Verneuil's disease is a chronic inflammatory skin disease of the follicles in apocrine glands rich area of the skin (axillary, inguinal, anogenital) and is associated with a deficient skin innate immunity. It is characterized by the occurrence of nodules, abscesses, fistulas, scars. Recently, vitamin D has been shown to stimulate skin innate immunity. OBJECTIVE: The primary objective of the study was to assess whether Verneuil's disease was associated with vitamin D deficiency. The secondary objective was to determine whether vitamin D supplementation could improve inflammatory lesions. METHODS: First, 25(OH) vitamin D3 serum levels in patients with Verneuil's disease followed at Nantes University Hospital were compared to those of healthy donors from the French Blood Bank. Then, a pilot study was conducted in 14 patients supplemented with vitamin D according to their vitamin D level at baseline at months 3 and 6. The endpoints at 6 months were decreased by at least 20% in the number of nodules and in the frequency of flare-ups. RESULTS: Twenty-two patients (100%) had vitamin D deficiency (level <30 ng/mL) of whom 36% were severely deficient (level <10 ng/mL), having correlation with the disease severity (P = 0.03268) vs. 20 controls with vitamin D deficiency (91%) of whom 14% were severely deficient. In 14 patients, the supplementation significantly decreased the number of nodules at 6 months (P = 0.01133), and the endpoints were achieved in 79% of these patients. A correlation between the therapeutic success and the importance of the increase in vitamin D level after supplementation was observed (P = 0.01099). CONCLUSION: Our study shows that Verneuil's disease is associated with a major vitamin D deficiency, correlated with the disease severity. It suggests that vitamin D could significantly improve the inflammatory nodules, probably by stimulating the skin innate immunity. A larger randomized study is needed to confirm these findings.

Evolution of clinical and molecular responses to bexarotene treatment in cutaneous T-cell lymphoma.

BACKGROUND: The mechanisms of action of bexarotene are not well understood. METHODS: A retrospective study on patients with cutaneous T-cell lymphoma (CTCL) treated with bexarotene was performed to see if bexarotene could act on the dominant T-cell clones. Thirty-five patients were included. Twenty-three were treated with bexarotene for more than 3 months (300 mg/m(2)). In 7 patients, phototherapy was given with bexarotene. RESULTS: Dominant T-cell clones were observed in 11 patients in peripheral blood and in 19 patients in skin. Our results demonstrate no significant evolution of T-cell clones either in skin or peripheral blood. Furthermore, the detection of T-cell clones in peripheral blood before starting bexarotene was significantly associated with the progression of the disease. UV therapy given with bexarotene significantly improved therapeutic response without any correlation with T-cell clones. CONCLUSION: This is the first study on the evolution of the T-cell clone in blood and skin in CTCL patients during bexarotene therapy.

Addition of zinc and manganese to a biological dressing.

BACKGROUND: Zinc and manganese, which are used in vivo because of their healing properties, have been shown to modulate in vitro integrin expression and to enhance keratinocyte migration. In addition, at the clinical level, a dressing of keratinocytes suspended in a fibrin glue has been proposed for the treatment of chronic wounds. OBJECTIVE: To investigate whether the addition of trace elements to this dressing could modulate the migratory phenotype of keratinocytes via the modulation of integrin expression in a manner similar to an in vitro model and thus increase the healing properties of this dressing. METHODS: Keratinocytes were mixed with Tissucol and maintained in culture for 12 days in a medium either supplemented or not with zinc or manganese. Then, integrin expression was studied by immunohistochemistry on fibrin clot cryosections. RESULTS: We observed a significant increase of alpha5beta1 with zinc compared to the control medium. Zinc also enhanced alphaVbeta6 expression and manganese alpha5beta1, alphaVbeta5 and alphaVbeta6 expression, however without reaching a significant level. CONCLUSION: By modulating integrin expression, trace elements can improve the efficiency of a biological dressing made of keratinocytes in a fibrin glue matrix and, thus, it appears beneficial to add them to this biological dressing for the treatment of skin defects.

Interest of the association retinaldehyde/glycolic acid in adult acne.

BACKGROUND: Topical retinoids have been successfully used in the treatment of acne vulgaris but may induce irritation when used twice daily. The association of retinaldehyde (RAL) with glycolic acid (GA) have complementary activities, which could be of interest for adult women with acne because of a better tolerance/efficacy ratio. The aim of this study was to evaluate the tolerance and the efficiency of RAL (0.1%)/GA (6%) in adult women with acne when used alone or in combination with their usual acne products except retinoids. METHODS: Three hundred ninety-seven women with acne (aged between 30 and 40 years old) were included in this open multicentric study. They had to apply cream containing RAL/GA for 90 days without stopping their previous acne treatment (except topical retinoids). The tolerance was the main criteria and the second one is the efficacy, which was assessed by counting inflammatory and retentional lesions after 30 and 90 days of treatment. RESULTS: Used alone or in association with other anti-acne treatments, RAL/GA was considered to be highly tolerated. A significant decrease in both inflammatory and retentional lesions between day 0 and day 90 indicates that RAL/GA can be used as monotherapy for mild acne or could potentate the efficiency of other anti-acne products used at the same time by patients suffering from moderate acne. Complaints about side-effects were rare. The subjective evaluation of the preparation's efficacy by investigators and patients was strongly favourable. CONCLUSION: These data show that a combination of RAL 0.1% and GA 6% may be used in association with other topical anti-acne treatments with an excellent tolerance.

[Acne, pregnant women and zinc salts: a literature review]. / Acné de la femme enceinte et sels de zinc: revue de la littérature.

BACKGROUND: Acne in adult women is a common reason for dermatological consultation. Dermatologists are occasionally confronted with the problem of treating acne in women who are either pregnant or seeking to become pregnant, or in breast-feeding women, in whom zinc salts are the only form of systemic treatment that may be envisaged. PATIENTS AND METHODS: The purpose of our study was to provide an overview of existing data concerning the use of the zinc salts in pregnant and breast-feeding women based on a literature review, a survey of prescription of zinc gluconate by French dermatologists, and finally, analysis of French pharmacovigilance data. RESULTS: There are many studies involving the use of zinc supplements during pregnancy. In these studies, more than 2500 pregnant women were given zinc at different doses. None of these studies described any abnormalities, congenital malformation, harmful effects or risk for the foetus associated with the use of zinc during pregnancy at doses below 75 mg/day. Although there are fewer studies of the use of zinc supplements in breast-feeding women, no abnormalities associated with use of zinc during breast-feeding have been reported. According to the results of the prescription survey, around 10,000 pregnant women and 2000 breast-feeding women are treated each year for acne using zinc gluconate, with only four serious adverse events involving zinc being reported since the initial introduction of the product, and with zinc having a doubtful causal relationship. DISCUSSION: Zinc plays a key role in our body's physiology, since it is involved in the activities of many enzymes. In addition, zinc requirements increase during pregnancy, mainly because of its utilisation during embryogenesis and fetal development. This literature review shows that use of zinc salts in pregnant women is beneficial in those with zinc deficiency but that it has no harmful effects in those without zinc deficiency.

Effect of selenium intake on the prevention of cutaneous epithelial lesions in organ transplant recipients.

Organ graft recipients have a high rate of pre-malignant and malignant epithelial lesions. Selenium directly influences the number of Langer-hans cells. In several studies selenium has shown its role in preventing various carcinomas, it was worth investigating whether it could prevent skin cancer linked to human papilloma virus (HPV). A multicentre, randomised, placebo-controlled, parallel group study in 184 recent organ transplant recipients was undertaken. Patients were treated for 3 years with 200 mug/day selenium (91 patients) or a matching placebo (93 patients), and then monitored for 2 years. Occurrence rates of warts and various keratoses (main criterion) and of skin cancers (secondary criterion) were compared in the two groups, using Kaplan-Meyer analyses. There was no difference between the two groups for the main criterion (odds-ratio 1.09, p = 0.72) or the secondary criterion (odds-ratio 3.08; p = 0.15). When both arms were pooled, phenotype and age were not found to be discriminatory factors, whereas a previous history of an actinic keratosis significantly increased the risk of developing a skin cancer by 17.5%. Safety was good and similar in both groups. Selenium was not shown to prevent the occurrence of skin lesions linked to HPV. The occurrence of skin cancer was higher if there had been a previous actinic keratosis, highlighting the importance of early dermatological follow-up of the transplanted population. This was demonstrated by the high rate of epithelial lesions detected, which was more than twice the rate usually reported in the literature.

Topical retinaldehyde with glycolic acid: study of tolerance and acceptability in association with anti-acne treatments in 1,709 patients.

BACKGROUND: Retinaldehyde (RAL), a key metabolite between vitamin A and retinoic acid, acts by modulating differentiation and proliferation of keratinocytes, which is of interest in acne lesions, mainly retentional lesions. Glycolic acid increases the exfoliation of corneocytes explaining its mild activity on retentional lesions. Thus, RAL and glycolic acid combined in the same product (Diacneal) have complementary activities which can be of interest for acne patients. The aim of this study was to evaluate the tolerance of Diacneal used by 1,709 acne patients in combination with their usual acne products except retinoids. RESULTS: This study demonstrated a very good tolerance of Diacneal when used with other acne treatments for 90 days. Complaints about side-effects were rare. Moreover, the significant decrease in both inflammatory and retentional lesions between day 0 and day 90 indicates that Diacneal could amplify the efficiency of other anti-acne products used at the same time by the patients. The subjective evaluation of the preparation's efficacy by investigators and patients was strongly favourable. CONCLUSION: These data show that a combination of RAL 0.1% and glycolic acid 6% may be used in association with other topical anti-acne treatments (benzoyl peroxide and topical antibiotics) with an excellent tolerance.

Prognostic factors in Sézary syndrome: a study of 28 patients.

BACKGROUND: The new European Organization for Research and Treatment of Cancer classification considers Sézary syndrome (SS) among the aggressive epidermotropic cutaneous T-cell lymphomas (ECTLs). Recent technological advances have facilitated the diagnosis of this disease, but it remains practically incurable, with a median survival of about 2.5-5 years. Deaths are due in part to the iatrogenic effects of treatments, which suggests that the management of SS could be improved. OBJECTIVES: Retrospectively to study the prognostic criteria related to disease progression. METHODS: Thirty patients with SS were followed up in the Dermatology Department of the University Hospital in Nantes, France, between January 1989 and May 2000. The diagnosis of SS was based on at least three of the following criteria: erythroderma, histological evidence of ECTL, a level of 20% or more circulating Sézary cells, and loss of My7 antigen expression by basal cells of the epidermis. Two patients not seen again after the initial diagnosis were excluded from the statistical study. RESULTS: The median disease-specific survival of the 28 patients was 64.55 +/- 10.11 months. The prognostic factors found in univariate analysis were age at diagnosis (P = 0.0109), interval before diagnosis (P = 0.0566), lactate dehydrogenase (LDH) level (P = 0.042) and presence of the Epstein-Barr virus (EBV) genome (BHLF in in situ hybridization) in skin (P = 0.0079). The prognostic factors found in multivariate analysis were age, interval before diagnosis and presence of the EBV genome in keratinocytes. A decreased number of Langerhans cells in the epidermis did not appear to be a prognostic factor. CONCLUSIONS: Our study confirms the prognostic value of age and LDH level, and for the first time demonstrates the prognostic value of the identification of the EBV genome in the skin. This seems consistent with a marked immune deficit during severe forms of SS.

Serum selenium in melanoma and epidermotropic cutaneous T-cell lymphoma.

As several studies have demonstrated a relationship between decreased serum selenium concentrations and the frequency of certain cancers, we studied these concentrations in two kinds of cutaneous tumour cancer: melanoma and epidermotropic cutaneous lymphoma. We first determined the predictive value of the selenium assay for the frequency of recurrences in stage I and II melanomas and then considered the relationship between serum selenium concentrations before treatment and therapeutic response. Two hundred melanomas (81 stage I, 63 stage II, 56 stage III) and 51 epidermotropic cutaneous T-cell lymphomas (CTCL) (8 stage I, 24 stage II, 10 stage III, 9 stage IV) were included in the study. Selenium assays were performed by atomic absorption spectrophotometry (92 +/- 16 micrograms/l in 30 normal subjects). Our study showed decreased serum selenium concentrations for melanoma (81 +/- 27 micrograms/l) and lymphoma (78 +/- 36 micrograms/l) relative to disease severity. The concentration was significantly lower (76 +/- 22) for stage I and II melanomas with recurrence within 2 years (31 patients), compared to those without recurrence (113 patients) (p < 0.05). Before treatment, it was higher in CTCL with good response to treatment (89 +/- 36) than in those without response (62 +/- 30) (p < 0.01). This study thus demonstrates the prognostic value of selenium assays in the follow-up of melanoma and CTCL.

Keratinocyte T6 antigen expression after PUVA therapy.

We report T6 antigen expression on keratinocytes in 11 cutaneous T lymphomas treated by PUVA therapy. This staining was absent before treatment. T6 reactivity was strictly limited to cell membrane. The nature of this expression is discussed, and it is suggested that it could be attributed to a passive diffusion from Langerhans's cells.