Chloracne: a case series on cutaneous expression of CYP1A1 as diagnostic biomarker.

Chloracne, also known as metabolizing acquired dioxin-induced skin hamartomas (MADISH), is a rare disfiguring disease related to dioxin exposure. There is a paucity of literature on the clinical manifestations and pathogenesis of chloracne/MADISH. The aim of this study was to assess the clinical features of this very unusual acneiform eruption and to explore the pathogenesis of the disease. This was a retrospective, observational report study was conducted on five patients belonging to the same nuclear family (father, mother and three children) and a relative (father's brother) living in the same house. Histopathological, immunohistochemical, laboratory and toxicological analyses were performed for all patients. The results suggest that CYP1A1 in human skin is a diagnostic biomarker in chloracne, and was positive for all the patients in our sample. Tetrachlorodibenzo-p-dioxin is the most investigated dioxin responsible for chloracne; however, several other agonists, whether dioxin-like or not, can activate the aryl hydrocarbon receptor. To our knowledge, this Italian case series is the first study to suggest polychlorinated biphenyls as a possible cause of an overstimulation of aryl hydrocarbons causing the consequent acneiform eruption.

Microcomedones in non-lesional acne prone skin New orientations on comedogenesis and its prevention.

BACKGROUND: In non-lesional skin of acne patients, cyanoacrylate skin surface stripping can harvest a structure called microcomedone (MC) which is the earliest phase of comedogenesis; the root of any subsequent clinical lesion and a target for the prevention of acne relapses. More information is needed on the putative biochemical contributors (biomarkers) of comedogenesis expressed in MC. METHODS: Proteins expressed in MC were screened by proteomics, immunohistochemistry and Western blotting. The in vitro effects of a comedolytic Silybum marianum fruit extract (SMFE) were studied in sebocyte cultures by RNA-Seq and modulation of CYP1A1 by qPCR and enzymatic activity. MC severity was correlated to lesions counts and keratin expression during 48 weeks in 23 acne patients using a topical comedolytic formulation containing SMFE. RESULTS: Two infundibular keratins, K75 and K79, co-localized in MC with the sebocyte progenitor cell marker LRIG1 and were used as a biomarker of comedogenesis for the follow-up of patients. In cultured sebocytes exposed to SMFE (i) transcriptomic analysis showed an up-regulation by a factor of 15 of RNA coding for K75 and (ii) the gene expression and catalytic activity of CYP1A1 under exposure to dioxin was decreased. In the acne patients using SMFE, the MC index in non-lesional skin decreased over time and remained until the 48th week, significantly lower than that of the first week. There was a high correlation between the decrease of MC index and the decrease and stability of the clinical lesions counts over time. Importantly, a low MC index status was found to be associated with a significant higher K75 expression in microcomedones. DISCUSSION: These observations provide new orientations on the mechanism of comedogenesis and its prevention. Maintaining a low MC status in non-lesional skin is a sound target for the prevention of acne relapse and a good sentinel of acne remissions.

RASopathic comedone-like or cystic lesions induced by vemurafenib: a model of skin lesions similar but not identical to those induced by dioxins MADISH.

BACKGROUND: Patients treated with vemurafenib for metastatic melanoma often develop skin lesions similar to those observed after exposure to dioxin-like compounds. We previously called these lesions MADISH (metabolizing acquired dioxin-induced skin hamartoma) when analysing a case of acute dioxin poisoning. OBJECTIVE: We performed a clinical trial aimed at comparing the skin lesions observed under vemurafenib treatment with MADISH in order to bring to light a possible crosstalk between vemurafenib and dioxin pathways. METHODS: In this case series study, we explored the histological aspect of skin lesions in 10 cases treated with vemurafenib for malignant melanoma. We also analysed the ability of vemurafenib and tyrosine kinase inhibitors to induce dioxin-AhR pathway. RESULTS: All patients had skin lesions diagnosed as 'non-inflammatory acneiform eruption' by dermatologists. These were predominantly facial with notable retroauricular involvement and clinically compatible with chloracne/MADISH when assessed by dioxin expert. Histological analysis showed mostly comedone-like lesions and dermal cysts containing epithelial wall with basal or lateral epithelial projections and lamellar keratinization and alterations of remaining sebaceous glands. The expression of CYP1A1, a gene highly induced following dioxin exposure, was not observed in these lesions. Vemurafenib and the tyrosine kinase inhibitors erlotinib and gefitinib did not induce CYP1A1 activity. DISCUSSION: Although the skin lesions under vemurafenib treatment were morphologically similar to MADISH, the absence of CYP1A1 expression in dermal cysts of patients and the absence of CYP1A1 activation by vemurafenib led us consider that these skin lesions were different from true MADISH and not mediated by a crosstalk of AhR signalling, but rather to a hyperactivation of PI3K-Akt pathway as a consequence of vemurafenib treatment. A strong expression of CYP1A1 in the epithelial wall of dermal cysts must be required, parallel to the morphology of the lesions, to make the diagnosis of MADISH, the hallmark of an exposure to dioxin-like/chloracnegen compounds.

A simple self-diagnosis tool to assess the prevalence of dermatoporosis in France.

IMPORTANCE: The term dermatoporosis has been proposed to describe clinical signs and functional consequences of age-related extreme skin fragility. OBJECTIVE: To create a simple dermatoporosis self-diagnosis tool (IDA: Index Dermatoporosis Assessment) and to use this tool to estimate the prevalence of dermatoporosis in France. DESIGN, SETTING AND PARTICIPANTS: A specific dermatoporosis questionnaire was developed with the help of senior dermatologists and survey experts. This questionnaire was submitted to consecutive individuals aged ≥65 years who consulted a dermatologist. At the end of the consultation, the dermatologist was asked to assess 'whether or not' dermatoporosis was present. In a second step, the final questionnaire was mailed to a representative sample of the French population aged ≥65 years in order to estimate the prevalence of dermatoporosis. RESULTS: The initial questionnaire, consisting of two modules (24 questions), was validated in 173 individuals aged ≥65 years) during a dermatologist consultation. Dermatologists diagnosed 46% of the individuals with dermatoporosis. The final validated questionnaire consisted of 14 items, 12 consisting in presence or absence of clinical signs and two items consisting of the self-assessment by individuals of skin ageing on neckline and hands (none/moderate/significant/very significant). A scoring system was generated to quote quantitatively dermatoporosis (from 0 if no sign of dermatoporosis to 20 maximal dermatoporosis). The area under the receiver operator curve was 0.8535, indicating a very good ability of the questionnaire to differentiate between individuals. A cut-off value of 11 was linked to positive and negative predictive values of 0.78 and 0.81, respectively. In a second step, using the questionnaire in a representative sample of the French population (n = 533), the estimated overall prevalence of dermatoporosis was 37.5% in French subjects aged ≥65 years [27.5% (males) vs. 43.9% (females); P < 0.05]. The estimated prevalence of dermatoporosis was twice higher in subjects with eczema or atopic dermatitis during childhood than in the population without dermatoporosis (60.6% vs. 33.4%, P < 0.001). Individuals with dermatoporosis also reported a higher prevalence of itching, long-term corticosteroid use, anticoagulant use and prior sun exposure. CONCLUSIONS AND RELEVANCE: Using a new simple dermatoporosis self-diagnosis tool, this study provides a previously unprecedented insight into the high prevalence of dermatoporosis in elderly individuals. IDA questionnaire is a short (14-item) and easy to use tool for evaluating dermatoporosis in adults and may allow an easy evaluation of each subject.

[Calcinosis cutis associated with connective tissue diseases]. / Calcinose cutanée associée aux connectivites.

Calcinosis cutis is characterized by calcified deposits in the skin and in subcutaneous tissues. The potential complications are ulceration, infection, functional limitation. According to serum calcium/phosphate levels, calcinosis cutis is classified in 4 subtypes: dystrophic, metastatic, iatrogenic, idiopathic. In dystrophic calcinosis, calcium/phosphate serum levels are within range. Dystrophic calcinosis occurs in damaged tissues and is associated with several connective tissue diseases (mainly systemic sclerosis and dermatopolymyositis). Its physiopathology remains unclear. Despite different therapeutic modalities in the litterature, there is no standard therapy for calcinosis. Thus, larger controlled studies are necessary.

Use of imatinib in a patient with cutaneous vasculopathy in the context of von Recklinghausen disease/neurofibromatosis.

von Recklinghausen disease/neurofibromatosis (NF) is caused by an autosomal dominant mutation in NF1, resulting in a deficiency of neurofibromin 1, a protein with a tumour suppressor function in the Ras-extracellular regulated kinase pathway. The disease comprises a variety of clinical manifestations, including vascular abnormalities. Large vessel abnormalities are well known, while small vessels of the skin are very rarely involved. The latter can cause livedo, necrosis and painful ulcers. For such ulcers, all invasive therapies (e.g. surgery and radiotherapy) are harmful and should be avoided. Herein, we describe a patient with NF and cutaneous vasculopathy treated with imatinib, a tyrosine kinase inhibitor.

A toxicological and dermatological assessment of alkyl cyclic ketones when used as fragrance ingredients. RIFM Expert Panel.

The alkyl cyclic ketone (ACK) fragrance ingredients are a diverse group of structures with similar metabolic and toxicity profiles. ACK fragrance materials demonstrate low acute toxicity. Upon repeat dose testing, some adverse effects in biochemical and hematological parameters, and slightly increased liver and kidney weights were reported, primarily at high doses, resulting from adaptive effects. Developmental effects occurred only in the presence of maternal toxicity. Assays in bacteria and mammalian cell systems and the mouse micronucleus assay did not demonstrate genotoxicity. ACK fragrance ingredients are considered non-irritating to the skin of humans; results showed few reactions, most of which were equivocal or involved doses greater than those in consumer products. Mild to moderate eye irritation in animal tests was observed with most compounds; however, full recovery was usually observed. Human sensitization studies indicate that ACK fragrance ingredients have a low sensitization potential. Diagnostic patch-tests indicated low sensitizing potential in humans; except for fragrance materials which caused reactions at 1% or 5%. Phototoxicity and photosensitization were not demonstrated in humans, and, with the possible exception of acetyl cedrene, would not be expected. It is concluded that ACK materials do not present a safety concern at current levels of use as fragrance ingredients.

The potential depigmenting activity of retinaldehyde.

BACKGROUND: Retinoids have been reported to exert depigmenting activity. Unlike most depigmenting agents that target tyrosinase, they are not phenolic agents and may act via different mechanisms. OBJECTIVES: We analysed the properties of retinaldehyde (RAL), a precursor of retinoic acid (RA), as a skin-lightening agent in various models. METHODS: The viability and the depigmenting properties of RAL were assessed in murine melanocytes, in human reconstructed epidermis, and in mice and guinea pigs. The melanin content and cytotoxicity were assessed in melanocytes; in 3-dimensional models, the melanin concentration and the number of active melanocytes were determined. RESULTS: RAL was taken up by melanocytes and mostly metabolised to retinol and retinyl esters, and to a lesser extent to RA. RAL decreased the melanin concentration of guinea pig ears and mouse tails by 54 and 74%, respectively, and decreased the number of active melanocytes by 42 and 77%, respectively. In reconstructed epidermis the melanin concentration was increased by 52%, whereas the number of active melanocytes decreased by 44%. CONCLUSION: RAL exerts a significant depigmenting activity with a mode of action that looks different from that of RA. Our data suggest a skin-lightening effect related to a melanolytic action (i.e. a decrease in melanin concentration, whatever the mechanism) rather than to melanocytotoxicity, besides other still unknown actions of RAL on melanocytes.

The combination of a retinoid, a phenolic agent and an antioxidant improves tolerance while retaining an optimal depigmenting action in reconstructed epidermis.

BACKGROUND: Cutaneous pigmented lesions urge the need to find safe and effective treatments to lighten the skin. OBJECTIVE: The aim of this study was to combine a retinoid (retinaldehyde), a new phenolic agent (4-(1-phenylethyl)-resorcinol) and a proreducing agent (δ-tocopheryl-ß-D-glucopyranoside) to achieve synergistic actions for skin lightening. METHODS: The tolerance profile and the depigmenting properties of these agents were assessed in murine keratinocyte and melanocyte cell lines, as well as in a 3-dimensional model of reconstructed epidermis. RESULTS: Retinaldehyde and 4-(1-phenylethyl)-resorcinol induced a significant decrease of tissue viability in reconstructed epidermis, but this cytotoxicity was prevented by the addition of δ-tocopheryl-ß-D-glucopyranoside. The combination of the three agents was, however, efficient in decreasing the specific melanin content and the density of active melanocytes. CONCLUSION: A combination of various chemicals acting via different mechanisms allows a decrease in the toxicity of each compound alone while retaining optimal skin-lightening properties.

Mortality rate in bullous pemphigoid: a retrospective monocentric cohort study.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease and is associated with an increased mortality. The end points of our study were to evaluate the mortality rate in a retrospective cohort of BP patients followed up to 5 years after the diagnosis and to determine prognostics factors. METHODS: All new cases of BP diagnosed between 1990 and 2003 in the University Hospital of Geneva were retrospectively collected. 60 patients were included, 47 (88.6%) of whom were treated with a combination of corticosteroids and chlorambucil. RESULTS: The 1-year, 2-year and 5-year probabilities of death were 26.7, 37.1 and 60.8%, respectively. Old age, dementia and use of chlorambucil at initial doses of 6 mg/day, but not at lower doses, were associated with poor prognosis in multivariate analysis. CONCLUSION: Our study confirms that BP is associated with a high mortality. The observed mortality rates are however higher than those of previous studies, which is probably related to the inclusion of more debilitated patients.

A toxicologic and dermatologic assessment of cyclopentanones and cyclopentenones when used as fragrance ingredients.

The cyclopentanone and cyclopentenone group of fragrance ingredients was critically evaluated for safety following a complete literature search. For high end users, calculated maximum dermal exposures vary from 0.002% to 15.16% in hydroalcoholic products; systemic exposures vary from 0.0003 to 0.7122 mg/kg/day. The cyclopentanones and cyclopentenones had a low order of acute toxicity and no significant toxicity in repeat dose studies. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. Developmental toxicity was not observed. Minimal evidence of skin irritation in humans is associated with current levels of use. Eleven materials were tested undiluted for eye irritation; three were considered irritants. No phototoxic and photosensitization reactions were seen with nine materials tested. At concentrations higher than current reported use, 14 materials were non-sensitizing in HRIPT or maximization tests. 2-Hexylidene cyclopentanone, 2-heptylidenecyclopentan-1-one and 3-methyl-2-(pentyloxy)-2-cyclopenten-1-one are weak sensitizers and have IFRA Standards. Risk of sensitization to the cyclopentanones and cyclopentenones is generally small under current levels of use. The Panel is of the opinion that there are no safety concerns for the cyclopentanones and cyclopentenones at reported levels of use and exposure as fragrance ingredients.

A toxicological and dermatological assessment of aryl alkyl alcohol simple acid ester derivatives when used as fragrance ingredients.

The aryl alkyl alcohol simple acid ester derivatives (AAASAE) group of fragrance ingredients was critically evaluated for safety following a complete literature search of the pertinent data. For high end users, calculated maximum skin exposures vary widely from 0.01% to 4.17%. AAASAE exhibit a common route of primary metabolism by carboxylesterases resulting in the formation of the simple acid and an aryl alkyl alcohol. They have low acute toxicity. No significant toxicity was observed in repeat-dose toxicity tests. There was no evidence of carcinogenicity of benzyl alcohol when it was administered in the feed; gavage studies resulted in pancreatic carcinogenesis due to the corn oil vehicle. The AAASAE are not mutagenic in bacterial systems or in vitro in mammalian cells, and have little to no in vivo genotoxicity. Reproductive and developmental toxicity data show no indication of adverse effects on reproductive function and NOELs for maternal and developmental toxicity are far in excess of current exposure levels. The AAASAE are generally not irritating or sensitizing at the current levels of exposure. The Panel is of the opinion that there are no safety concerns regarding the AAASAE at the current levels of use and exposure.

A toxicological and dermatological assessment of aryl alkyl alcohols when used as fragrance ingredients.

The aryl alkyl alcohol (AAA) fragrance ingredients are a diverse group of chemical structures with similar metabolic and toxicity profiles. The AAA fragrances demonstrate low acute and subchronic dermal and oral toxicity. No carcinogenicity in rats or mice was observed in 2-year chronic testing of benzyl alcohol or α-methylbenzyl alcohol; the latter did induce species and gender-specific renal adenomas in male rats at the high dose. There was no to little genotoxicity, mutagenicity, or clastogenicity in the mutagenic in vitro bacterial assays, and in vitro mammalian cell assays. All in vivo micronucleus assays were negative. NOAELs for maternal and developmental toxicity are far in excess of current human exposure levels. At concentrations likely to be encountered by consumers, AAA fragrance ingredients are non-irritating to the skin. The potential for eye irritation is minimal. With the exception of benzyl alcohol and to a lesser extent phenethyl and 2-phenoxyethyl AAA alcohols, human sensitization studies, diagnostic patch tests and human induction studies, indicate that AAA fragrance ingredients generally have no or low sensitization potential. Available data indicate that the potential for photosensitization is low. It is concluded that these materials would not present a safety concern at current levels of use as fragrance ingredients.

Recommendations for the treatment of nail psoriasis in patients with moderate to severe psoriasis: a dermatology expert group consensus.

BACKGROUND: Nail involvement is common in psoriasis patients and is often associated with severe disease. Patients with nail psoriasis experience pain, functional impairment and social stigma, with significant restriction of daily activities and quality of life. However, nail psoriasis often goes untreated, as many physicians believe it is difficult to treat, despite the availability of effective treatment options. Clinical data and guidelines for managing and treating psoriasis patients with both skin and nail symptoms are limited. OBJECTIVE: To prepare recommendations for the management and treatment of patients with moderate to severe psoriasis with nail involvement. METHODS: A collaborative Delphi survey was used to obtain consensus on current practice in the management of nail disease in patients with moderate to severe psoriasis from an expert panel of 11 dermatologists from Europe and Canada with substantial clinical expertise in managing these patients. Agreement was defined utilizing a Likert scale of 1-9. Consensus regarding agreement was an interquartile range (IQR) ≥ 7; consensus regarding disagreement was an IQR ≤ 3. RESULTS: The expert panel addressed several topics including burden of disease, nail assessment, treatment goals and treatment options. The panel agreed that: it is extremely important to assess nail involvement in patients with psoriasis; nail assessments are rarely performed in routine clinical practice; full skin and nail clearance is an achievable goal with appropriate systemic therapy in patients with moderate to severe psoriasis with nail involvement. CONCLUSION: This article provides useful and practical considerations for the management and treatment of patients with moderate to severe skin and nail psoriasis.

A toxicological and dermatological assessment of macrocyclic ketones when used as fragrance ingredients: the RIFM Expert Panel.

The macrocyclic ketone (MK) group of fragrance ingredients was evaluated for safety following a complete literature search. For high end users, calculated maximum dermal exposures vary from 0.13% to 1.10%; systemic exposures vary from 0.0005 to 0.0441 mg/kg/day. The MKs had low acute toxicity and no significant repeat dose toxicity. Liver weight and blood biochemistry effects were reversible after 2 weeks. No genotoxicity in bacteria and mammalian cell lines was observed. Reproductive toxicity was not observed for 3-methylcyclopentadecenone in an OECD compliant study. In humans, MKs are generally not irritating after one application. Animal studies showed irritation for some materials at concentrations higher than current consumer exposure. At rates consistent with current human exposure, phototoxicity and photosensitization were not observed. In animals, some MKs are sensitizers only at concentrations of 20%, 30%, or 100%, which are higher than current consumer exposure. No evidence of sensitization was observed in human tests. In patients with fragrance allergy, reactions were seen with cyclopentadecanone (3/178). Based on these findings, the Panel is of the opinion that there are no safety concerns for the MKs at reported levels of use and exposure as fragrance ingredients.

A toxicologic and dermatologic assessment of cinnamyl phenylpropyl materials when used as fragrance ingredients.

The cinnamyl phenylpropyl fragrance ingredients are a diverse group of chemical structures that have similar metabolic and toxicity profiles. A toxicological and dermatological review of these fragrance ingredients is presented. The common characteristic structural element of cinnamyl phenylpropyl materials is an aryl substituted primary alcohol/aldehyde/ester. For high end users, calculated maximum dermal exposures vary from 0.14% to 0.72%; systemic exposures vary from 0.0002 to 0.0280 mg/kg/day. Human dermatological studies show that these materials are not generally irritants or sensitizers at lower exposures from consumer products. Reactions (0.9%) in fragrance sensitive patients were observed with 3-phenyl-1-propanol at 5% in petrolatum. The cinnamyl phenylpropyl materials had low acute toxicity and no significant toxicity in repeat dose oral or dermal toxicity studies. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. The cinnamyl phenylpropyl alcohol materials participate in the same beta oxidation pathways as their parent cinnamic acid derivatives, including common routes of absorption, distribution, and metabolic detoxification, and exhibit similar toxicological endpoints. Based on the review of available data, it is concluded that these materials would not present a safety concern at current levels of use as fragrance ingredients.