Summary
Background
Transcription factor retinoic acid‐related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)‐17A and IL‐17F expression. IL‐17A plays a central role in the pathogenesis of ...several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF‐06763809 has been hypothesized to inhibit IL‐17A production in T‐helper 17 (Th17) cells, thereby reducing psoriasis symptoms.
Aim
To assess the safety, tolerability and effect on skin infiltrate thickness of PF‐06763809 in participants with mild/moderate chronic plaque psoriasis.
Methods
This was a randomized, double‐blind, first‐in‐human study (trial registration: ClinicalTrials.gov NCT03469336). Participants received each of the following six treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF‐06763809, a vehicle and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness echo‐poor band (EPB) on ultrasonography at Day 19, and safety. Change in psoriasis‐associated gene expression (Day 19), evaluated by real‐time reverse transcription PCR of skin biopsies, was an exploratory endpoint.
Results
In total, 17 participants completed the study. Change from baseline in the EPB on Day 19 for all three doses of PF‐06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P < 0.0001). Treatment‐related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF‐06763809‐treated skin lesions.
Conclusion
Using a psoriasis plaque test design, PF‐06763809 was found to be well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers.
Summary
Background
Oral phosphodiesterase (PDE)4 inhibitors have shown efficacy in chronic obstructive pulmonary disease and psoriasis.
Objectives
To assess the effectiveness, local safety and ...tolerability, and systemic pharmacokinetics of two topical PDE4 inhibitors, roflumilast and TAK‐084, in plaque psoriasis.
Methods
An intraindividual comparison of six topical products was made in 15 patients aged 18–65 years with stable chronic plaque psoriasis in an investigator‐blinded, within‐subject randomized study. The products evaluated were calcipotriol 0·005% cream; betamethasone valerate 0·1% (both in their marketed formulations); investigational cream formulations of roflumilast 0·5% and TAK‐084 0·5% and 5%; and a vehicle cream formulation as a control. Each treatment was applied daily to different test sites located on psoriasis plaques for 3 weeks.
Results
The primary end point of (mean) change from baseline in skin infiltrate thickness after 3 weeks of treatment showed statistically significant improvements for all treatments: betamethasone valerate cream (−286·9 μm), the selective PDE4 inhibitors roflumilast 0·5% (−237·1 μm) and TAK‐084 (0·5% cream, −153·6 μm; 5% cream, −216·7 μm) and calcipotriol 0·005% (−187·7 μm) when compared with vehicle cream control (all P < 0·001). Both the TAK‐084 5% and roflumilast 0·5% formulations performed well overall compared with the potent corticosteroid, betamethasone, and were ranked better than the vitamin D analogue calcipotriol. All adverse events were mild or moderate and none was serious.
Conclusions
Topical treatment with cream formulations of the PDE4 inhibitors roflumilast and TAK‐084 reduced inflammation, measured as a change in skin infiltrate thickness, and reduced psoriasis severity. Corticosteroid treatments have known systemic and cutaneous side‐effects; PDE4 inhibitors could offer an alternative to these and deserve further study.
What's already known about this topic?
Topical administration of several products to different areas of psoriatic plaques on the same patient have been used previously to differentiate between different potencies, formulations and concentrations of both topical corticosteroids and calcipotriol.
Oral small‐molecule phosphodiesterase (PDE)4 inhibitors show anti‐inflammatory activity.
What does this study add?
A modified psoriasis plaque test is described in which multiple intraindividual comparisons were made to detect differences between products and doses in a small number of patients.
Topical applications of selective PDE4 inhibitors to psoriasis plaques were well tolerated. Anti‐inflammatory activity and clinical improvements were observed with both PDE4 inhibitors tested, and the effects were dose dependent.
The test is a useful clinical model to compare the effects of different topical treatments during early clinical development.
Linked Comment: Heng. Br J Dermatol 2016; 175:455–456.
Objective
During the development of cosmetic formulations, in vitro and in vivo methods are essential tools used to reliably assess the skin irritation potential of a product or ingredient. ...Epicutaneous patch testing (single and/or multiple application protocols) has long been used as an initial in vivo method to screen for possible skin irritation properties of a substance or formulation. To confirm the mildness and dermatological and/or consumer acceptance of a product, use tests are often subsequently conducted. A study was therefore initiated to see how well patch test results correlate with use tests with respect to irritation elicited by skincare (leave‐on) products.
Methods/results
A number of different cosmetic formulations were assessed in both tests. Although the patch test results did not indicate substantial irritation potentials, immediate‐type reactions (stinging and redness) were observed in some volunteers which disappeared within approx. 1 h. Although transient, these reactions suggested that consumer acceptance would probably be low and the studies were discontinued. Immediate‐type reactions are rare but have been described for some substances used in cosmetics. These unexpected results were nevertheless intriguing and prompted the start of a journey to see if patch test protocols could be modified to assess these reactions. An occlusive short‐term patch test protocol with an application period of 20 min was developed. Successful identification of the spontaneous reactions became possible. Furthermore, there was a correlation between the intensity of reactions observed in the short‐term patch test and those observed in the controlled in‐use studies. Short‐term patch testing using the developed protocol can therefore reliably be used as a screening method, for example in the development and optimization of cosmetic formulations containing ingredients that could cause spontaneous reactions, for instance of non‐immunological contact urticaria type.
Conclusion
The lessons learned from this studies indicate that simple modifications of existing test protocols can lead to important insights into skin reactions. These modifications can then be used to create further building blocks in the development and optimization of test strategies for cosmetic formulations which offer reliable study designs for possible reactions product developers may encounter.
Résumé
Objectif
Lors du développement de formulations cosmétiques, les méthodes in vitro et in vivo sont des outils essentiels utilisés pour évaluer de manière fiable le potentiel d'irritation cutanée d'un produit ou d'un ingrédient. Le test épicutané (protocoles d'application uniques et / ou multiples) est utilisé depuis longtemps comme méthode initiale in vivo pour dépister les éventuelles propriétés d'irritation cutanée d'une substance ou d'une formulation. Afin de confirmer la douceur et l'acceptation dermatologique et / ou consommateur d'un produit, des tests d'usage sont souvent effectués ultérieurement. Une étude a donc été initiée pour voir dans quelle mesure les résultats des tests épicutanés correspondent aux tests d'usage en ce qui concerne l'irritation provoquée par les produits de soin (sans rinçage).
Méthodes/Résultats
Un certain nombre de formulations cosmétiques différentes ont été évaluées dans les deux tests. Bien que les résultats du test épicutané n'indiquent pas de potentiels d'irritation substantiels, des réactions de type immédiat (picotements et rougeurs) ont été observées chez certains volontaires. Celles‐ci ont disparu en à peu près 1 heure. Bien que transitoires, ces réactions de type 5 suggéraient que l'acceptation du consommateur serait probablement faible et les études ont été interrompues. Les réactions de type immédiat 6 sont rares mais ont été évoquées en relation avec certaines substances utilisées en cosmétique. Ces résultats inattendus étaient néanmoins intrigants et ont incité le lancement d’un processus pour voir si les protocoles de test épicutané pouvaient être modifiés pour évaluer ces réactions. Un protocole de test épicutané à court terme occlusif avec une période d'application de 20 min a été développé, permettant l'identification réussie des réactions spontanées. Il a été de plus constate une corrélation entre l'intensité des réactions observées dans le test épicutané à court terme et celles observées dans les test d’usage contrôlés. Le test épicutané à court terme utilisant le protocole développé peut donc être utilisé de manière fiable comme méthode de dépistage, par exemple dans le développement et l'optimisation de formulations cosmétiques contenant des ingrédients qui pourraient provoquer des réactions spontanées, par exemple de type urticaire de contact non immunologique.
Conclusion
Les leçons tirées de ces études indiquent que de simples modifications des protocoles de test existants peuvent révéler des informations importantes sur les réactions cutanées. Ces modifications peuvent ensuite être utilisées pour créer d'autres blocs de construction dans le développement et l'optimisation de stratégies de test pour des formulations cosmétiques qui offrent des conceptions d'études fiables pour les réactions possibles que les développeurs de produits peuvent rencontrer.
Although the 24‐h epicutaneous patch testing is routinely used as a screening method in the development and optimization of cosmetic formulations, it does not allow all reactions to be assessed and surprises can be encountered. A number of ingredients can cause spontaneous although transient reactions, such as redness possibly indicative of reaction such as non‐immunological contact urticaria. As these reactions are transient and usually reside resolve within 1–2 h, typical ECT protocols do not allow detection of immediate‐type reactions, but simple modifications of existing test protocols can lead to important insights into skin reactions.
Summary
Background The barrier perturbation pattern and molecular markers of inflammation upon tandem repeated irritation in chronologically aged skin have not been previously studied.
Objectives ...We aimed to investigate the barrier impairment kinetic and in vivo cytokine profile following sequential irritation with sodium lauryl sulfate (SLS) and undiluted toluene (Tol) in aged compared with young skin.
Methods Four fields on the volar forearm of healthy aged and young volunteers (median age, respectively, 63·9 and 32·6 years) were sequentially exposed to 0·5% SLS and undiluted toluene in a controlled tandem repeated irritation test; an adjacent nontreated field served as control. The permeability barrier function was monitored by repeated measurements of transepidermal water loss (TEWL), capacitance and erythema every 24 h up to 96 h. The stratum corneum cytokines were harvested by sequential tape stripping and quantified by multiplex bead array and enzyme‐linked immunosorbent assay.
Results Compared with young skin, aged skin was characterized by delayed and/or less pronounced alterations in the visual irritation score, TEWL, chromametry a*‐value and capacitance, assessed by the respective Δ‐values for each parameter and monitoring time point. In both groups, exposure to SLS/SLS, SLS/Tol and Tol/SLS resulted in decreased interleukin (IL)‐1α levels, whereas the application of Tol/Tol induced an increase in IL‐1α. Furthermore, decreased IL‐1 receptor antagonist (IL‐1RA) levels and a lower IL‐1RA/IL‐1α ratio were found following repeated exposure to the irritants.
Conclusions Our results provide evidence for selective alterations in the cytokine profile and distinct barrier impairment kinetic following tandem repeated irritation with SLS and Tol in aged compared with young skin in vivo.
The actual advantage of barrier creams over bland emollients for skin protection is still hotly debated. In a randomized, double‐blinded study, a newly‐introduced barrier cream and its moisturizing ...vehicle were compared regarding their skin compatibility, efficacy and resulting acceptance. Thus, 2 panels of 25 hospital nurses with mild signs of skin irritation were asked to use 1 of the test products provided (verum or vehicle) over a period of 4 weeks. Effects of both types of preparations were studied weekly by clinical examination and the instrumental assessment of bioengineering parameters. Results showed no significant differences between barrier cream and vehicle. In both groups, clinical skin status improved and stratum corneum hydration increased significantly during the study period. Both preparations were tolerated and accepted well, thus showing both skin protection and skin care. These results contribute to the debate as to whether a strict distinction between “skin care” and “skin protection” products is justified. The vehicle alone is capable of positively influencing skin status. Emphasis must be laid on regular, frequent, and correct application of a product for it to be effective.
In clinical practice, cutaneous exposure to a variety of irritants such as surfactants and solvents is frequent. Although the induction of irritant dermatitis by single irritants has been extensively ...studied in recent years, our knowledge of the effects of simultaneous application of different irritants is limited. Using non‐invasive techniques for measurements of transepidermal water loss (TEWL) and skin colour reflectance, we quantified the irritant effects of single and concurrent application of 0·5% sodium lauryl sulphate (SLS) and undiluted toluene (TOL) in vivo. The irritants were applied twice daily for 30 min to the volar forearms of 20 volunteers. Repeated application of SLS and TOL induced an irritant reaction, as indicated by an increase in TEWL and skin redness. In contrast to SLS alone, the application of TOL alone induced only a moderate increase in TEWL, confirming previous results. Concurrent application of SLS/TOL and TOL/SLS induced significantly stronger reactions than those caused by twice daily application of each irritant on its own. Our results demonstrate that a mixed application of an anionic detergent and an organic solvent has an additive effect on skin irritation. It is suggested that pretreatment with SLS causes an increased susceptibility to TOL irritation and vice versa. Thus, the necessity for special precautions against skin absorption of TOL when handling detergents such as SLS is emphasized.
Background: There is still a lack of standardization of the atopy patch test (APT) in test procedures and evaluation methods. Our aim was to examine the reproducibility of APT results and to compare ...visual evaluation to chromametry and laser Doppler imaging.
Methods: Fifty‐two volunteers with atopic eczema/dermatitis syndrome (AEDS) were included. The APT was performed on tape‐stripped and unstripped test fields on their backs using cat dander, house dust mite and grass pollen allergens from two different suppliers. Responders were re‐tested 4–12 weeks later with the same allergens on their forearms.
Results: Using Allergopharma allergens, 14 (26.9%) volunteers showed one or more positive reactions. The reproducibility rate was 56.3%. The Erlangen atopy score in APT‐positive and negative volunteers was 19 ± 6 vs 15 ± 6. The test agreement in volunteers tested with both allergens, from Allergopharma and Stallerge`nes, was poor. Correlation of the results between the three evaluation methods was significant (P ≤ 0.001).
Conclusions: The low reproducibility rate of APT results and the poor inter‐test‐agreement using allergens from different suppliers show that much work remains to make the APT a reliable tool in identifying relevant aeroallergens that lead to flare ups of AEDS. Compared to chromametry and laser Doppler imaging, visual scoring was superior in differentiation between irritative and allergic reactions.
Although skin protective products to prevent irritant skin reactions are in wide use, neither standardized test models to prove differences in efficacy exist, nor has the quality or the ...reproducibility of results been evaluated in a multicentre approach. This should be mandatory when developing or testing skin care products. Therefore, we have designed a multicentre study in an approach to find a standardized test procedure for the evaluation of skin protective products. In this irritation study, a repeated short‐time occlusive irritation test (ROIT) with a standardized protocol has been evaluated in 2 phases (12 days and 5 days protocol) in 4 (n=20) respectively 6 (n=33) skilled centres. The skin reaction was induced by 2 irritants (0.5% aq. SLS and toluene, 2× a day for 30 min). Its modification by 3 different cream bases with different hydrophilicity was analyzed. The irritation was monitored by bioengineering methods (TEWL measurement, colorimetry) and by clinical scoring. The evaluation showed that significant results could already be achieved with the 5‐day protocol. Furthermore, in spite of the expected inter‐centre variations due to heterogeneity of the individual threshold of irritation, interpretation of clinical score, and inter‐instrumental variability, the ranking of the vehicles regarding reduction of the irritant reaction was consistent in all centres.
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