A systematic review and network meta-analysis of topical pharmacological, oral pharmacological, physical and combined treatments for acne vulgaris.

BACKGROUND: Various treatments for acne vulgaris exist, but little is known about their comparative effectiveness in relation to acne severity. OBJECTIVES: To identify best treatments for mild-to-moderate and moderate-to-severe acne, as determined by clinician-assessed morphological features. METHODS: We undertook a systematic review and network meta-analysis of randomized controlled trials (RCTs) assessing topical pharmacological, oral pharmacological, physical and combined treatments for mild-to-moderate and moderate-to-severe acne, published up to May 2020. Outcomes included percentage change in total lesion count from baseline, treatment discontinuation for any reason, and discontinuation owing to side-effects. Risk of bias was assessed using the Cochrane risk-of-bias tool and bias adjustment models. Effects for treatments with ≥ 50 observations each compared with placebo are reported below. RESULTS: We included 179 RCTs with approximately 35 000 observations across 49 treatment classes. For mild-to-moderate acne, the most effective options for each treatment type were as follows: topical pharmacological - combined retinoid with benzoyl peroxide (BPO) [mean difference 26·16%, 95% credible interval (CrI) 16·75-35·36%]; physical - chemical peels, e.g. salicylic or mandelic acid (39·70%, 95% CrI 12·54-66·78%) and photochemical therapy (combined blue/red light) (35·36%, 95% CrI 17·75-53·08%). Oral pharmacological treatments (e.g. antibiotics, hormonal contraceptives) did not appear to be effective after bias adjustment. BPO and topical retinoids were less well tolerated than placebo. For moderate-to-severe acne, the most effective options for each treatment type were as follows: topical pharmacological - combined retinoid with lincosamide (clindamycin) (44·43%, 95% CrI 29·20-60·02%); oral pharmacological - isotretinoin of total cumulative dose ≥ 120 mg kg-1 per single course (58·09%, 95% CrI 36·99-79·29%); physical - photodynamic therapy (light therapy enhanced by a photosensitizing chemical) (40·45%, 95% CrI 26·17-54·11%); combined - BPO with topical retinoid and oral tetracycline (43·53%, 95% CrI 29·49-57·70%). Topical retinoids and oral tetracyclines were less well tolerated than placebo. The quality of included RCTs was moderate to very low, with evidence of inconsistency between direct and indirect evidence. Uncertainty in findings was high, in particular for chemical peels, photochemical therapy and photodynamic therapy. However, conclusions were robust to potential bias in the evidence. CONCLUSIONS: Topical pharmacological treatment combinations, chemical peels and photochemical therapy were most effective for mild-to-moderate acne. Topical pharmacological treatment combinations, oral antibiotics combined with topical pharmacological treatments, oral isotretinoin and photodynamic therapy were most effective for moderate-to-severe acne. Further research is warranted for chemical peels, photochemical therapy and photodynamic therapy for which evidence was more limited. What is already known about this topic? Acne vulgaris is the eighth most common disease globally. Several topical, oral, physical and combined treatments for acne vulgaris exist. Network meta-analysis (NMA) synthesizes direct and indirect evidence and allows simultaneous inference for all treatments forming an evidence network. Previous NMAs have assessed a limited range of treatments for acne vulgaris and have not evaluated effectiveness of treatments for moderate-to-severe acne. What does this study add? For mild-to-moderate acne, topical treatment combinations, chemical peels, and photochemical therapy (combined blue/red light; blue light) are most effective. For moderate-to-severe acne, topical treatment combinations, oral antibiotics combined with topical treatments, oral isotretinoin and photodynamic therapy (light therapy enhanced by a photosensitizing chemical) are most effective. Based on these findings, along with further clinical and cost-effectiveness considerations, National Institute for Health and Care Excellence (NICE) guidance recommends, as first-line treatments, fixed topical treatment combinations for mild-to-moderate acne and fixed topical treatment combinations, or oral tetracyclines combined with topical treatments, for moderate-to-severe acne.

Hydrogel composite containing azelaic acid and tea tree essential oil as a therapeutic strategy for Propionibacterium and testosterone-induced acne.

Azelaic acid (AzA) is a USFDA bioactive prescribed against acne vulgaris. It possesses delivery challenges like poor aqueous solubility, low skin-penetrability, and dose-dependent side effects, which could be overcome by its synergistic combination with tea tree oil (TTO) as a microemulsion (ME)-based hydrogel composite. AzA-TTO ME was prepared to employ pseudo-ternary phase diagram construction. The best AzA-TTO ME was of uniform size (polydispersity index < 0.7), nano-range (~357.4 ± 2% nm), transmittance (> 90%), and negative zeta potential (-1.42 ± 0.25% mV) values. ME hydrogel composite with optimum rheological and textural attributes showed better permeation, retention, and skin-compliant characteristics, vis-a-vis marketed formulation (Aziderm™) when evaluated in Wistar rat skin. In vitro antibacterial efficacy in bacterial strains, i.e., Staphylococcus aureus, Propionibacterium acne, and Staphylococcus epidermidis, was evaluated employing agar well plate diffusion and broth dilution assay. ME hydrogel has shown an increase in zone of inhibition by two folds and a decrease in minimum inhibitory concentration (MIC) by eightfold against P. acnes vis-a-vis AzA. Finally, ME hydrogel composite exhibited a better reduction in the papule density (93.75 ± 1.64%) in comparison to Aziderm™ 72.69 ± 4.67%) on acne as developed in rats by inducing testosterone. Thus, the developed AzA-TTO ME hydrogel composite promises an efficacious and comparatively safer drug delivery system for the topical therapy of acne vulgaris.

Endocrine Disrupting Chemicals, Hormone Receptors, and Acne Vulgaris: A Connecting Hypothesis.

The relationship between endocrine disrupting chemicals (EDCs) and the pathogenesis of acne vulgaris has yet to be explored in the literature. Acne vulgaris is a chronic inflammatory skin disease of the pilosebaceous unit. The pathogenesis of acne involves several hormonal pathways, including androgens, insulin-like growth factor 1(IGF-1), estrogens, and corticosteroids. EDCs influence these pathways primarily through two mechanisms: altering endogenous hormone levels and interfering with hormone receptor function. This review article describes the mechanistic links between EDCs and the development of acne lesions. Highlighted is the contributory role of androgen receptor ligands, such as bisphenol A (BPA) and mono-2-ethylhexyl Phthalate (MEHP), via upregulation of lipogenic genes and resultant exacerbation of cholesterol synthesis. Additionally discussed is the protective role of phytoestrogen EDCs in counteracting androgen-induced sebocyte maturation through attenuation of PPARy transcriptional activity (i.e., resveratrol) and restoration of estrogen-regulated TGF-B expression in skin cells (i.e., genistein). Examination of the relationship between EDCs and acne vulgaris may inform adjunctive avenues of treatment such as limiting environmental exposures, and increasing low-glycemic, plant-rich foods in the diet. With a better understanding of the cumulative role that EDCs play in acne, clinicians can be better equipped to treat and ultimately improve the lives of their patients.

Acne related to dietary supplements.

Multiple prescription medications may cause or aggravate acne. A number of dietary supplements have also been linked to acne, including those containing vitamins B6/B12, iodine, and whey, as well as "muscle building supplements" that may be contaminated with anabolic-androgenic steroids (AAS). Acne linked to dietary supplements generally resolves following supplement discontinuation. Lesions associated with high-dose vitamin B6 and B12 supplements have been described as monomorphic and although pathogenesis is unknown, a number of hypotheses have been proposed. Iodine-related acne may be related to the use of kelp supplements and has been reported as monomorphic, inflammatory pustules on the face and upper trunk. Whey protein supplements, derived from milk and used for bodybuilding, are associated with papulonodular acne involving the trunk and sometimes the face. Finally, AAS-induced acne has been described as acne fulminans, acne conglobata, and acne papulopustulosa. With studies indicating that about half of US adults report using dietary supplements, it is important that dermatologists directly ask acne patients about their supplement use and educate them on the potential risks of even seemingly innocuous dietary supplements.

Dermatologic care of the transgender patient.

Literature is limited regarding the medical and cosmetic dermatologic issues pertinent to transgender patients and the reasons why 19 transgender individuals seek care from dermatologists. Clinical management of this population has historically been limited to 20 mental health providers, endocrinologists, and select surgeons with expertise in sex reassignment surgery. The impact of hormonal 21 therapy on transgender skin has been well documented in endocrinology journals, but is underrepresented in dermatology 22 literature. Hormonal therapy leads to drastic skin alterations, impacting sebum production, hair growth, and acne, all of which may 23 become a dermatologic concern for the transgender patient. Dermatologists may also be consulted regarding issues such as 24 permanent hair removal, androgenic alopecia, or scar revision following breast reduction surgery or genital reassignment surgery. 25 The purpose of this review is to provide relevant information for use by all dermatology providers who care for transgender 26 patients or patients undergoing transition.

Acne and whey protein supplementation among bodybuilders.

Accumulative evidence supports the role of nutritional factors in acne. I report here 5 healthy male adult patients developing acne after the consumption of whey protein, a favorite supplement of those engaged in bodybuilding. These observations are in line with biochemical and epidemiological data supporting the effects of milk and dairy products as enhancers of insulin/insulin-like growth factor 1 signaling and acne aggravation. Further prospective studies are required to determine the possible role of dietary supplements in the fitness and bodybuilding environment.

Whey protein precipitating moderate to severe acne flares in 5 teenaged athletes.

Acne vulgaris has been linked to milk ingestion, both whole and skim milk. The milk fraction that promotes acne is unknown. Five case reports are presented of male patients aged 14 to 18 years who experienced onset of acne shortly after initiation of whey protein supplementation; 3 teenagers used the supplement for muscle building in football training and the other 2 for attempting to gain weight. All 5 patients had poor response to acne treatment regimens of oral antibiotics, topical retinoids, and benzoyl peroxide. Lesions fully cleared in 4 patients after discontinuation of whey protein supplementation, but 1 patient's acne flared after reinitiation of the whey protein supplement. Two patients did not immediately discontinue whey protein supplementation; 1 of them cleared after he discontinued whey protein during his second course of isotretinoin and 1 was lost to follow-up. Among these patients, at least 6 different brands of whey protein supplementation had been used, including whey protein shakes and reconstituted powders. Whey protein may be the fraction of dairy products that promote acne formation. Larger studies are needed to determine the mechanism of comedogenesis.

A mechanism-based classification of dermatologic reactions to biologic agents used in the treatment of cutaneous disease: Part 1.

Biologic therapies are an efficacious new method of controlling a number of chronic conditions. Data regarding these medications continues to emerge, giving clinicians a greater understanding of their side effects profiles. The biologic agents used in dermatology, particularly the tumor necrosis factor-alpha inhibitors, have a number of varied dermatologic side effects. In this two-part article, we perform a review of literature regarding the cutaneous side effects of infliximab, etanercept, adalimumab, rituximab, efalizumab, and alefacept. In Part 1, we will discuss cutaneous infections, malignancy, rebound phenomenon, eczema, atopic dermatitis, lichenoid reactions, granulomatous disease, pruritus, acne, and progressive multifocal leukoencephalopathy.

[Management of acne in women over 25 years of age]. / Manejo del acné en mujeres mayores de 25 años.

Acne is one of the most widespread skin diseases in the general population and among adolescents in particular. However, it is becoming increasingly common in patients over 25 years of age, and particularly in women. We distinguish 2 types of post adolescent acne: persistent acne--the most frequent such acne--is an extension of acne that began in adolescence and continues into adulthood, and late-onset acne, which first appears in those over 25 years. We review the clinical characteristics of these types of acne in women, the causes, the recommended complementary tests, and the particulars of treatment in order to adequately manage this condition.

Manejo del acné en mujeres mayores de 25 años / Management of Acne in Women Over 25 Years of Age

El acné es una de las enfermedades de la piel de mayor prevalencia en general y en la adolescencia en particular. Sin embargo, cada vez es más frecuente ver pacientes mayores de 25 años, especialmente mujeres, afectados por el proceso. Distinguimos dos tipos de acné postadolescente: el «acné persistente», el más frecuente, continuación del acné iniciado en la adolescencia y que permanece en la edad adulta, y el «acné de comienzo tardío», que aparece por primera vez en los mayores de 25 años. Revisamos las características clínicas de estos tipos de acné en las mujeres, los factores etiológicos implicados, las pruebas complementarias necesarias y las peculiaridades a la hora de tratarlos, para conseguir un correcto manejo de estas pacientes (AU)

Acne is one of the most widespread skin diseases in the general population and among adolescents in particular. However, it is becoming increasingly common in patients over 25 years of age, and particularly in women. We distinguish 2 types of postadolescent acne: persistent acne—the most frequent such acne—is an extension of acne that began in adolescence and continues into adulthood, and late-onset acne, which first appears in those over 25 years. We review the clinical characteristics of these types of acne in women, the causes, the recommended complementary tests, and the particulars of treatment in order to adequately manage this condition (AU)

Photocontact dermatitis and chloracne: two major occupational and environmental skin diseases induced by different actions of halogenated chemicals.

Among occupational and environmental disorders, contact or photocontact dermatitis and an acneiform eruption are two major skin disorders. Photocontact dermatitis was historically caused by various halogenated salicylanilides, while the acne is induced by halogenated aromatic hydrocarbons and thus called chloracne. Therefore, it should be noted that halogenated chemical compounds are important causative agents in the occupational and environmental medicine. In photocontact dermatitis, photoconjugation of epidermal cells with a photohaptenic halogenated chemical is the initial step. Langerhans cells serve as antigen-presenting cells and T cells sensitized by photoantigen-bearing Langerhans cells induce this photosensitivity. On the other hand, in chloracne, halogeneted hydrocarbons render keratinocytes of the outer root sheath and sebaceous duct hyperplastic. The dilated infundibulum of most hair follicles is then filled with comedone that consist of many accumulated layers of keratinized cells and sebum. Therefore, halogenated chemicals exhibit different actions, i.e. the induction of an immunologic consequence and the modulation of keratinocyte biology. These two conditions also provide good experimental models for investigating dermatology.

Dehydroepiandrosterone for the treatment of systemic lupus erythematosus.

The adrenal steroidal hormone dehydroepiandrosterone (DHEA) has been studied as a potential pharmacological agent in the treatment of the autoimmune disease systemic lupus erythematosus (SLE). Both the endocrine effects (the ability to be converted peripherally to androgenic and oestrogenic sex steroids) and the immunomodulatory effects of DHEA (the production of the Th(1) cytokines, such as IL-2) suggest that this hormone could be of benefit for patients with SLE. During the past decade, five controlled clinical trials and a number of additional observational studies have been performed investigating these possibilities. The results from these studies suggest that 200 mg/day of DHEA for 7 - 12 months decreases corticosteroid requirement for the patients, the frequency of disease flares, has an anti-osteoporotic effect and has an overall beneficial effect on SLE disease activity in female patients. A small study suggested benefits for cognitive function in such patients. The side effects acne and hirsutism were seen relatively frequently (30 - 40% and 10 - 12% of patients, respectively) but in most instances were deemed mild. DHEA treatment resulted in changes in lipid profile and may have endocrine effects, the consequences of which will need to be ascertained through longer-term follow-up studies.

[Acute acne fulminans et conglobata after the end of high-dose testosterone therapy for hereditary tall stature]. / Akute Akne fulminans et conglobata nach Beendigung einer hochdosierten Testosterontherapie bei konstitutionellem Hochwuchs.

We report on a 13.2 years old boy who was treated for tall stature (expected target height of 204.8 +/- 5.4 cm) with high dose of testosterone. Therapy for height reduction was started with testosterone injections (250 mg Testoviron Depot i.m.) once a week. There occurred no side effects during 6 months of treatment. Maximal blood testosterone concentration was 1209 ng/dl (norm: 300-1000 ng/dl). After six months height reduction was successful with a final height of 192.7 cm. Four weeks after cessation of therapy a severe acne conglobata et fulminans appeared in the face, the back and the breast lacking any familial predisposition for acne or other skin diseases. The exacerbation was accompanied by decreased endurance, nausea and indisposition. Leucocytosis with left shift, elevation of blood sedimentation rate and C-reactive protein in addition with an increase of immunglobulin G (IgG) were detectable. At that time testosterone concentration was 192 ng/dl. Systemic treatment was started with isoretretinoin therapy (retinoid 13-cis retinacid (Roaccutan) 0.3 mg/kg), 8 mg methylprednisolon (Urbason) and cefaclor (Panoral). Local therapy included external disinfectants. After 4 months of treatment infection parameters disappeared and the acne healed with visible skin defects and severe scars. This is the first case report on acne conglobata et fulminans that appeared after cessation of testosterone therapy. High testosterone treatment seems to trigger the outbreak of sex hormone related skin disorders such as acne fulminans. It can be presumed that testosterone leads to longer lasting induction of androgen receptors resulting in acne fulminans even four weeks after treatment. Patients asking for hormonal height reduction should be aware of this rare but serious side effect.

Dehydroepiandrosterone in systemic lupus erythematosus: relationship between dosage, serum levels, and clinical response.

OBJECTIVE: To examine in women with systemic lupus erythematosus (SLE) who participated in a clinical trial the relationship between daily dose of dehydroepiandrosterone (DHEA), serum levels of DHEA and DHEA sulfate (DHEAS), clinical effectiveness, and side effects. METHODS: Twenty-three women with mild to moderate SLE were treated with DHEA for a 6 month period. The starting dose was 50 mg/day, and monthly stepwise increases were allowed. Subjects were assessed monthly by the Systemic Lupus Erythematosus Disease Activity Index, Systemic Lupus Activity Measure (SLAM), Health Assessment Questionnaire, and other outcomes. Serum testosterone, DHEA, and DHEAS levels were obtained and side effects noted monthly. RESULTS: Statistically significant improvements were found in all lupus outcomes over 6 months. Serum DHEA and DHEAS levels correlated with the dose of DHEA. Serum DHEA and DHEAS correlated negatively with SLAM score. A second order regression analysis of serum DHEAS level versus SLAM score suggested that the optimal serum level of DHEAS was 1000 microg/dl. The most common side effect was acne. CONCLUSION: The clinical response to DHEA was not clearly dose dependent. Serum levels of DHEA and DHEAS correlated only weakly with lupus outcomes, but suggested an optimum serum DHEAS of 1000 microg/dl. Monitoring these serum levels appears to have limited clinical utility.

Metabolic and behavioral effects of high-dose, exogenous testosterone in healthy men.

In addition to their use as replacement therapy for hypogonadal males, androgens, particularly testosterone (T), are being explored as potential hormonal male contraceptive agents, alone or in combination with other compounds. Androgens have regulatory effects on a variety of physiological systems in addition to gonadotropin secretion and spermatogenesis. Therefore, as hormonal contraceptive regiments that alter serum T levels are explored, it is important to evaluate their effects on these aspects of normal male physiology. The effects of exogenous T on suppression of spermatogenesis in 19 healthy men were recently compared, using a T dosage of 200 mg im/week for 20 weeks. Before treatment, the men were evaluated during a 3-month pretreatment period, and after treatment, they were followed for 4-6 months or until their sperm counts normalized. Because of the lack of information regarding the effects of exogenous T on nonreproductive physiology, we examined the effects of high-dose T on plasma lipids, calcium metabolism, and sexual behavior in our subjects. Mean serum T and estradiol levels increased significantly during the treatment period. Plasma high-density lipoprotein (HDL) cholesterol levels decreased significantly within the first month and remained suppressed during the duration of T administration. At the end of the treatment period, mean plasma HDL cholesterol had decreased by 13 +/- 2% (P < 0.05); plasma levels of HDL2, HDL3, and apoprotein AI also decreased significantly; mean levels of low density lipoprotein cholesterol and triglycerides were unchanged. After 1 month of the recovery period, plasma HDL levels had returned to the baseline range. Serum calcium levels decreased slightly during treatment; this decrease was statistically significant. Urinary calcium excretion did not change. Mean levels of serum intact PTH increased by 84 +/- 17% (P < 0.05) during T administration; in contrast, 25-hydroxyvitamin D levels decreased by 16 +/- 4% (P < 0.05), and 1,25-dihydroxyvitamin D levels did not change significantly. All markers of calcium metabolism returned to baseline during the posttreatment period. Little change was found in self-reported sexual and aggressive behaviors during the study. There was a trend toward increased arousal and spontaneous erections during T administration, but this did not reach statistical significance. Frequency of sexual intercourse, masturbation, and kissing and fondling did not change, nor was the subjects' satisfaction in their relationships affected by T administration. Mean body weight increased by 4.0 +/- 0.5 kg. Approximately half the men noted mild acne. Body weight and acne symptoms returned to baseline during the recovery period.(ABSTRACT TRUNCATED AT 400 WORDS)

Chloracne caused by ingestion of olive oil contaminated with PCDDs and PCDFs.

1. All members of a Spanish family (father, mother and six children) developed chloracne. 2. The causative agent was found to be the family's stock of olive oil, which had become contaminated with polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), pentachlorophenol, and hexachlorobenzene. 3. The more highly chlorinated PCDDs, in particular octachlorodibenzo-p-dioxin, were the predominant congeners in the oil. 4. Three members of the family exhibited either an overt or a sub-clinical disturbance of kidney function. The father also had a chronic respiratory problem. These changes could not be unequivocally attributed to the PCDDs. 5. Experimental toxicity of the oil was limited to the development of an hepatic porphyria in mice. 6. A serum sample, taken 5 years after consumption of the oil ceased, contained high levels of the PCDDs and PCDFs. Extrapolation back to ingested dose was used to validate dosage estimates. 7. The use of toxicity equivalence factors (TEFs) provided estimates of cumulative dosage to produce chloracne as 0.13-0.31 micrograms 2378-TCDD kg-1 (using EPA TEFs) or 6.7-16 micrograms 2378-TCDD kg-1 (using Nordic/NATO TEFs). 8. This is the first incident in which human toxicity is related primarily to ingestion of PCDDs and for which estimates of dosage can be made.