A revised action spectrum for vitamin D synthesis by suberythemal UV radiation exposure in humans in vivo.

Action spectra are important biological weighting functions for risk/benefit analyses of ultraviolet (UV) radiation (UVR) exposure. One important human benefit of exposure to terrestrial solar UVB radiation (∼295 to 315 nm) is the cutaneous synthesis of vitamin D3 that is initiated by the photoconversion of 7-dehydrocholesterol to previtamin D3 An action spectrum for this process that is followed by other nonphotochemical steps to achieve biologically active vitamin D3 has been established from ex vivo data and is widely used, although its validity has been questioned. We tested this action spectrum in vivo by full- or partial-body suberythemal irradiation of 75 healthy young volunteers with five different polychromatic UVR spectra on five serial occasions. Serum 25-hydroxyvitamin D3 [25(OH)D3] levels, as the most accurate measure of vitamin D3 status, were assessed before, during, and after the exposures. These were then used to generate linear dose-response curves that were different for each UVR spectrum. It was established that the previtamin D3 action spectrum was not valid when related to the serum 25(OH)D3 levels, as weighting the UVR doses with this action spectrum did not result in a common regression line unless it was adjusted by a blue shift, with 5 nm giving the best fit. Such a blue shift is in accord with the published in vitro action spectra for vitamin D3 synthesis. Thus, calculations regarding the risk (typically erythema) versus the benefit of exposure to solar UVR based on the ex vivo previtamin D3 action spectrum require revision.

The Effect on BSA of Proactive Management versus Reactive Management of Psoriasis With Fixed-Dose Cal/BD Foam in the PSO-LONG Study.

Reduction of psoriasis body surface area (BSA) is associated with improved patient quality of life. Post-hoc analyses of the PSO-LONG study compared impact on BSA of proactive management versus reactive management strategies using calcipotriol/betamethasone dipropionate (Cal/BD) foam. Mean BSA values, as well as normalized area under the curves (AUCs) for patient BSA were assessed. Analyses found that after the PSO-LONG study’s four-week open-label lead-in phase, when all patients received once-daily Cal/BD foam, mean BSA was significantly reduced. Thereafter, mean BSA remained at lower levels in patients on proactive management compared to reactive management. This was reflected in AUC BSA, which was consistently lower in the proactive management arm. Treatment-related differences were statistically significant when analyzing the full analysis set (FAS) population, as well as when restricting the analysis to study completers. Additional analyses restricted the dataset to include only observations from psoriasis remission periods, or periods of disease relapse. Treatment-related differences in AUC were statistically significant in observations during remission, but not during relapse. This could be expected given the trial’s design, wherein all patients who relapsed were offered the same rescue therapy with once daily Cal/BD foam. Similarly, for patients who dropped out, there was no treatment-related difference in mean BSA during the two weeks preceding dropout, likely due to the common occurrence of relapse in these patients. This paper found that proactive management, in addition to preventing more relapses as previously shown, also maintained BSA at a lower level during remission than reactive management. J Drugs Dermatol. 20(5):567-570. doi:10.36849/JDD.5870.

Treating Scalp Psoriasis with Calcipotriene/Betamethasone Dipropionate Fixed-dose Combination Cutaneous Foam: Review of Phase 2 Data

Two Phase 2 studies investigated the effect of a fixed-dose combination foam containing calcipotriene monohydrate (Cal) and betamethasone dipropionate (BD) on scalp psoriasis in adult and adolescent patients. Patients had psoriasis classified as at least 'mild' per PGA. NCT01536938 enrolled adult patients (≥18 years) randomized 1:1:1 to once-daily (QD) Cal/BD foam (Cal 0.005%, BD 0.064%), Cal foam (0.005%) or BD foam (0.064%). NCT02387853 enrolled adolescent patients (12- <17 years) to Cal/BD foam QD (dose as previously). Treatment success was based on improvement in PGA classification at week 4. Additional efficacy endpoints included mPASI in adults and effect on extent of scalp surface area (SSA) in adolescents. Safety was also assessed. Overall, 302 adults (n=100 Cal/BD foam; n=101 Cal foam; n=101 BD foam) and 106 adolescents received treatment. Treatment success in adults was significantly higher with Cal/BD vs Cal foam (53.0% vs 35.6%, P=0.021) and numerically higher than with BD foam (47.5%, P=0.45). Mean percentage changes in mPASI were -80.0%, -57.8% and -71.2%, for Cal/BD, Cal and BD foam, respectively. In adolescents, 73.6% of patients treated with Cal/BD foam achieved treatment success and mean SSA fell from 50.6% at baseline to 12.5% at week 4. All treatment-related AEs were considered mild-to-moderate across both studies, except one severe AE (hypersensitivity reaction with urticaria) in the adult Cal/BD foam group, which led to withdrawal from the study. In these studies, treatment of scalp psoriasis with Cal/BD foam provided good efficacy for adults and adolescents and was generally well tolerated. J Drugs Dermatol. 2020;19(8): doi:10.36849/JDD.2020.5168.

Pigment genes not skin pigmentation affect UVB-induced vitamin D.

Skin pigmentation is believed to contribute to the generally low serum 25-hydroxyvitamin D (25(OH)D) concentrations observed in darker-skinned persons. The influence of measured skin pigmentation on UVB-induced 25(OH)D increase was investigated together with 9 demographic and 13 genetic parameters (pigment SNPs). Forty participants representing a wide range in measured skin pigmentation were exposed to identical UVB doses on identical body areas over nine weeks with weekly measurements of serum 25(OH)D. This study took place in Denmark during winter, a period with negligible ambient UVB, so variation in 25(OH)D synthesis was not influenced by latitude, season, sun and clothing habits. The increase in 25(OH)D concentration displayed considerable variation (range: 2.9 to 139 nmol L-1). Constitutive and facultative skin pigmentation exerted separate influence on the variation of the UVB-induced linear 25(OH)D increase. However, this influence was statistically non-significant in the presence of separate significant pigment SNPs. The variation in the 25(OH)D increase in the combined linear model was not explained by measured skin pigmentation but by sex, height, age and seven SNPs located in the ASIP, MTAP, MIR196A29 and Solute Carrier Family genes. This linear model including individual intercepts and the 10 parameters influencing the slope explained 77.4% of the variation. This study confirmed the influence of sex, age and height on 25(OH)D increase and found that pigment genes provided a better relation to UVB-induced 25(OH)D increase compared to the actual measured skin pigmentation. Therefore, only investigating skin pigmentation obscures other causal parameters for low 25(OH)D.

Major inter-personal variation in the increase and maximal level of 25-hydroxy vitamin D induced by UVB.

Vitamin D influences skeletal health as well as other aspects of human health. Even when the most obvious sources of variation such as solar UVB exposure, latitude, season, clothing habits, skin pigmentation and ethnicity are selected for, variation in the serum 25-hydroxy vitamin D (25(OH)D) response to UVB remains extensive and unexplained. Our study assessed the inter-personal variation in 25(OH)D response to UVR and the maximal obtainable 25(OH)D level in 22 healthy participants (220 samples) with similar skin pigmentation during winter with negligible ambient UVB. Participants received identical UVB doses on identical body areas until a maximal level of 25(OH)D was reached. Major inter-personal variation in both the maximal obtainable UVB-induced 25(OH)D level (range 85-216 nmol l(-1), mean 134 nmol l(-1)) and the total increase in 25(OH)D (range 3-139 nmol l(-1), mean 48 nmol l(-1)) was found. A linear model including measured 25(OH)D baselines as personal intercepts explained 54.9% of the variation. By further including personal slopes in the model, as much as 90.8% of the variation could be explained. The explained variation constituted by personal differences in slopes thus represented 35.9%. Age, vitamin D receptor gene polymorphisms, height and constitutive skin pigmentation (a skin area not exposed to UVB) explained 15.1% of this variation. Despite elimination of most known external sources of variation, our study demonstrated inter-personal variation corresponding to an observed maximal difference of 136 nmol l(-1) in the total increase of 25(OH)D and 131 nmol l(-1) in the maximal level of 25(OH)D.

Sun exposure patterns of urban, suburban, and rural children: a dosimetry and diary study of 150 children.

BACKGROUND: Sun exposure is the main etiology of skin cancer. Differences in skin cancer incidence have been observed between rural and urban populations. OBJECTIVES: As sun exposure begins in childhood, we examined summer UVR exposure doses and sun behavior in children resident in urban, suburban, and rural areas. METHODS: Personal, electronic UVR dosimeters and sun behavior diaries were used during a summer (3.5 months) by 150 children (4-19 years of age) resident in urban, suburban, and rural areas. RESULTS: On school/kindergarten days rural children spent more time outdoors and received higher UVR doses than urban and suburban children (rural: median 2.3 h per day, median 0.9 SED per day, urban: median 1.3 h per day, median 0.3 SED per day, suburban: median 1.5 h per day, median 0.4 SED per day) (p ≤ 0.007). Urban and suburban children exhibited a more intermittent sun exposure pattern than rural children. Differences in UVR exposure doses were from high exposure days (e.g. beach days) outside Denmark. Suburban children had a total UVR exposure similar to rural children (suburban: median 109.4 SED, rural: median 103.1 SED), with days spent abroad contributing greatly to the total UVR exposure dose (total UVR on days spent abroad: suburban: median 48.0 SED, rural: median 8.0 SED). CONCLUSIONS: Differences in sun exposure patterns exist between children from different areas and may be the background for higher skin cancer incidences in urban populations.

Skin temperature during sunbathing--relevance for skin cancer.

It has been found that exposure to heat and infrared radiation (IR) can be carcinogenic, and that a combination of ultraviolet radiation (UVR) and IR possibly amplifies carcinogenesis. To investigate how the skin temperature is affected by sunbathing, we measured the skin temperature on 20 healthy volunteers over 6 days' sun holiday in Egypt. Temperatures were measured with an infrared thermometer gun at 8 skin sites on the volunteers while they were indoors in the morning and when sunbathing during the day. Skin temperatures were higher during sunbathing (33.5 °C ± 2.1 °C) (mean ± SD) than when indoors in the morning (32.6 °C ± 1.4 °C) (mean ± SD) (P < 0.0001). The average skin temperature for men was higher than for women by 0.40 °C in the morning (P = 0.02) and by 0.44 °C during sunbathing (P < 0.0001). Our results show that sunbathing has an impact on skin temperature, which possibly by activation of the heat shock response, is likely to contribute to the immediate and delayed effects of UV in a way that has to be found out in future studies.

Application of sunscreen--theory and reality.

We present research on sunscreen use with possible pitfalls and discuss theory vs. reality. A literature review in PubMed was conducted using the terms 'sunscreen application', 'sunscreen use' and 'sun protection factor'. The sun protection factor (SPF) of sunscreens are tested using a thickness of 2 mg/cm(2) , but investigations show that sunscreen under natural conditions is applied insufficiently with amounts about 0.39 to 1.0 mg/cm(2) , which decreases the protection factor considerably. It has been shown that early reapplication or use of very high SPF (70-100) may partly compensate for the discrepancy between the amounts of sunscreen applied during testing and in reality, and that sunscreen application can be improved by education of consumers. Missing areas and ultraviolet radiation exposure before sunscreen application are other pitfalls that reduce the protective effect of sunscreens considerably. Current sunscreen labelling overrates the protective effect of a given sunscreen when the reality of sunscreen use is taken into account. This may possibly mislead consumers to feel it is safe to extend sun exposure. Alternatively to educating people to use large amounts of sunscreen, we suggest a simple teaching strategy: (1) Apply before sun exposure and (2) Reapply once within 1 h.

Sunscreen use and failures--on site observations on a sun-holiday.

With this observation study we aimed to determine how and when sunscreen was used. 20 sun seekers were observed during a one-week sun holiday in Hurghada, Egypt. The sunscreen application thickness was related to part of body, time outdoors, exposure to ultraviolet radiation and to sunburning. Skin sites with sunscreen were exposed to UVR significantly longer and received significantly higher UVR doses than skin sites without sunscreen. They received an average of 0.62 SED [0.0-9.3 SED] (13% of their MED) before the first sunscreen application of the day. The average sunscreen used was SPF15 and the sunscreen application thickness was in average 0.79 mg cm(-)2 giving an approximated effect of SPF3. For different body parts either the total UVR exposure dose or the UVR exposure time and UVR exposure dose before the first sunscreen application were higher for sunburned than non-sunburned skin sites. In the final model gender, skin type and UVR to skin (adjusted for SPF and sunscreen application thickness) were significant predictors of sunburning. The sunscreen application thickness of 0.79 mg cm(-)2 was less than the 2 mg cm(-2) used for testing SPF. The late start of sunscreen use and improper application thickness was ineffective in preventing sunburn, and therefore could not compensate for the risk of prolonged UVR exposure and high UVR doses. Our results lead us to suspect that the protective effect of sunscreen use against DNA-damage, and thereby skin cancer, is minimal the way sunscreen is used under real sun holiday conditions.

A sun holiday is a sunburn holiday.

Many people take holidays in sunny locations with the express aim of sunbathing. This may result in sunburn, which is a risk factor for skin cancer. We investigated 25 Danish sun seekers during a week's holiday in the Canary Islands. The percentage of body surface area with sunburn was determined by daily skin examinations by the same observer. Erythemally effective ultraviolet radiation (UVR) exposure was assessed with time-stamped personal dosimeters worn on the wrist. Volunteers reported their clothing cover and sunscreen use in diaries, and this information was used to determine body site-specific UVR doses after adjustment for sun protection factor. Remarkably, we found that all volunteers sunburned at some point. The risk of sunburn correlated significantly with the adjusted body site-specific UVR dose. Furthermore, there was also a significant relationship between the daily UVR dose and percentage of body surface area with sunburn. Our study shows that holiday UVR exposure results in a high risk of sunburn, which potentially increases the risk of skin cancer. Possible protection by melanogenesis is insufficient to protect against sunburn during a 1-week sun holiday. Finally, our data clearly support a substantial skin cancer risk from sun holidays.

Sun behaviour and personal UVR exposure among Europeans on short term holidays.

Solar ultraviolet radiation (UVR) is known to be the main cause of skin cancer, the incidence of which is rising with national differences across Europe. With this observation study we aimed to determine the impact of nationality on sun behaviour and personal UVR exposure on sun and ski holidays. 25 Danish and 20 Spanish sun-seekers were observed during a sun holiday in Spain, and 26 Danish and 27 Austrian skiers were observed during a ski holiday in Austria. The participants recorded their location and clothing in diaries. Personal time-logged UVR data were recorded as standard erythema doses (SEDs) by an electronic UVR dosimeter worn on the wrist. Danish sun-seekers were outdoors for significantly longer, received significant higher percentages of ambient UVR, and received greater accumulated UVR doses than Spanish sun-seekers. Danish skiers were also outdoors for significantly longer than Austrian skiers, but the behaviour of the Danish skiers did not result in significantly greater accumulated UVR doses. Both Danish and Spanish sun-seekers and Danish and Austrian skiers received substantial UVR doses. The behaviour's influence on the UVR doses received by the Danish participants may indicate an explanation of the higher skin cancer incidence among Scandinavians compared with other European populations.

Sun exposure and protection behavior of Danish farm children: parental influence on their children.

Healthy sun habits acquired in childhood could reduce skin cancer incidence. We examined the sun exposure and protection behavior of an expected high-exposure group of children, and the association to their parents. Open, prospective cohort study. One hundred and thirty nine participants (40 families) kept daily sun behavior diaries (sun exposure, sunscreen use, sunburns) over a 4-month summer period (15,985 diary days). The Pigment Protection Factor (PPF), an objective measure of sun exposure, was measured at two body sites, before and after summer. All participants presented data from the same 115 days. Risk behavior (sun exposure of upper body) took place on 9.5 days (boys) and 15.6 days (girls). Sunburn and sunscreen use were infrequent. Boys' sun exposure resulted in an increased photo protection over the study period of 1.7 SED (upper arm) and 0.8 SED (shoulder) to elicit erythema. Corresponding values for girls were as follows: 0.9 SED (upper arm) and 0.5 SED (shoulder). Boys' sunscreen use correlated to their mothers' (r = 0.523, P = 0.02). Girls' number of risk days (r = 0.552, P = 0.005) and sun exposure (upper arm: r = 0.621, P < 0.001) correlated to their mothers'. The children's sun exposure was substantial. Only mothers influenced children's sun behavior and exposure. This may be of relevance in future sun protection campaigns.

Sun and ski holidays improve vitamin D status, but are associated with high levels of DNA damage.

Skin cancer is caused by solar UVR, which is also essential for vitamin D production. DNA damage (thymine dimers: T-T dimers) and vitamin D (25(OH)D) synthesis are both initiated by solar UVB. We aimed to investigate the simultaneous adverse and beneficial effects of solar UVB exposure in holidaymakers. Sun-seekers and skiers (n=71) were observed over 6 days through on-site monitoring, personal diary entries, and recording of personal UVB exposure doses with electronic dosimeters. Urine and blood samples were analyzed for T-T dimers and 25(OH)D, respectively. The volunteers had a statistically significant increase in vitamin D. There were strong associations between UVB exposure and post-holiday levels of T-T dimers and vitamin D, as well as between post-holiday T-T dimers and vitamin D. We conclude that UVB-induced vitamin D synthesis is associated with considerable DNA damage in the skin. These data, on two major health predictors, provide a basis for further field studies that may result in better understanding of the risks and benefits of "real life" solar exposure. However, vitamin D status can be improved more safely through the use of vitamin D dietary supplements.

[Dermatomyositis as a marker of lung cancer]. / Dermatomyositis som markør for lungecancer.

A 76-year-old female was referred because of violaceous dermatitis on sun-exposed skin. She had associated muscle weakness, dysphagia, dysarthria and reported an unintended weight loss. The clinical presentation gave a suspicion of dermatomyositis, and diagnostic procedures revealed a small-cell lung cancer. She was treated with prednisolone, chemotherapy and radiotherapy. Despite intended curative treatment, she died of the cancer six months later. This case emphasizes the importance of a thorough examination for an underlying cancer, in patients diagnosed with dermatomyositis.

Alitretinoin--its use in intractable hand eczema and other potential indications.

Chronic hand eczema is a significant cause of morbidity. A number of treatments are traditionally used, and often useful, but in spite of this a sizeable group of patients develop chronic recalcitrant hand eczema. Retinoids are known to influence keratinization and inflammation, and acitretin has shown some effect in the treatment of chronic hand eczema. Alitretinoin (9-cis-retinoic acid) is a panagonist retinoid binding to all six known retinoid receptors (RAR-alpha, -beta, -gamma and RXR-alpha, -beta, -gamma). Several studies have been carried out with this new drug, and it has been shown to be effective in 28% to 89% of patients with previously intractable hand eczema. In addition, alitretinoin appears to have some potential in the treatment of AIDS-related Kaposi sarcoma. Attempts to use the drug in secondary prophylaxis has shown some promise in former tobacco smokers, whereas no effect was seen in patients with cervical intraepithelial neoplasia. Currently, the primary therapeutic potential of alitretinoin appears to be the treatment of chronic recalcitrant hand eczema, which also forms a large and hitherto neglected group of patients.