Measurements of sun sensitivity in five European countries confirm the relative nature of Fitzpatrick skin phototype scale.

BACKGROUND/PURPOSE: Skin colour and sun sensitivity are highly related to the distance to the equator: people in southern latitudes are usually darker and less sensitive to sun than in northern latitudes. Whether differences in sun sensitivity can be found in a relatively homogenous European population is unclear. We aimed to objectively measure sun sensitivity (assessed as pigment protection factor (PPF)) in five European countries, relate it to self-assessed Fitzpatrick skin phototype (FST) and to determine whether PPF levels in the different FST categories are dependent on the investigated countries. METHODS: Volunteers (n = 569) were recruited in Copenhagen (Denmark), Dublin (Ireland), London (England), Münster (Germany) and Ioannina (Greece). Skin phototype was self-assessed using the FST scale. PPF was measured at both sun-protected buttocks and five sun-exposed skin sites by a skin reflectance spectrophotometer. RESULTS: Overall, there were statistically significant differences in PPF of the buttocks, inner arm, outer arm, forehead, chest and back between the five countries (P ≤ .031). Generally, PPF level was lower in northern than in southern latitudes. PPF of the buttocks was similar in all countries for those who identified as FST I (P = .723). However, it was statistically significantly different (P ≤ 2.913*10-4 ) and country-dependent for those who identified as FST II-IV. CONCLUSION: Objectively measured sun sensitivity is higher (lower PPF) in northern compared with southern latitudes. The choice of self-identified FST category is influenced by a person's immediate environment. Therefore, we confirmed the relative nature of the FST scale and the need to standardise the skin phototype assessment procedure.

Afamelanotide for Erythropoietic Protoporphyria.

BACKGROUND: Erythropoietic protoporphyria is a severe photodermatosis that is associated with acute phototoxicity. Patients with this condition have excruciating pain and a markedly reduced quality of life. We evaluated the safety and efficacy of an α-melanocyte-stimulating hormone analogue, afamelanotide, to decrease pain and improve quality of life. METHODS: We conducted two multicenter, randomized, double-blind, placebo-controlled trials of subcutaneous implants containing 16 mg of afamelanotide. Patients in the European Union (74 patients) and the United States (94 patients) were randomly assigned, in a 1:1 ratio, to receive a subcutaneous implant containing either afamelanotide or placebo every 60 days (a total of five implants in the European Union study and three in the U.S study). The type and duration of sun exposure, number and severity of phototoxic reactions, and adverse events were recorded over the respective 180-day and 270-day study periods. Quality of life was assessed with the use of validated questionnaires. A subgroup of U.S. patients underwent photoprovocation testing. The primary efficacy end point was the number of hours of direct exposure to sunlight without pain. RESULTS: In the U.S. study, the duration of pain-free time after 6 months was longer in the afamelanotide group (median, 69.4 hours, vs. 40.8 hours in the placebo group; P=0.04). In the European Union study, the duration of pain-free time after 9 months was also longer in the afamelanotide group than in the placebo group (median, 6.0 hours vs. 0.8 hours; P=0.005), and the number of phototoxic reactions was lower in the the afamelanotide group (77 vs. 146, P=0.04). In both trials, quality of life improved with afamelanotide therapy. Adverse events were mostly mild; serious adverse events were not thought to be related to the study drug. CONCLUSIONS: Afamelanotide had an acceptable side-effect and adverse-event profile and was associated with an increased duration of sun exposure without pain and improved quality of life in patients with erythropoietic protoporphyria. (Funded by Clinuvel Pharmaceuticals and others; ClinicalTrials.gov numbers, NCT01605136 and NCT00979745.).

Photoaggravated disorders.

Photoaggravated skin disorders are diseases that occur without UV radiation but are sometimes or frequently exacerbated by UV radiation. In conditions, such as lupus erythematosus, photoaggravation occurs in a majority of patients, whereas in conditions, such as psoriasis and atopic dermatitis, only a subset of patients demonstrate photoaggravation. Polymorphous light eruption is a common photodermatosis in all skin types, making it important to differentiate photoaggravation of an underlying disorder, such as lupus erythematosus, from superimposed polymorphous light eruption. Disease-specific treatments should be instituted where possible. A key component of management of photoaggravated conditions is photoprotection with behavioral change, UV-protective clothing, and broad-spectrum sunscreen.

Photosensitizing medications and photocarcinogenesis.

Photosensitivity is an exaggerated or abnormal response to ultraviolet (UV) or visible light exposure. Many current medications are known photosensitizers; however, the effects of the sensitization can be subclinical and go unnoticed by the person affected. While some of these drugs are used for short and defined periods, others are used indefinitely for the treatment of chronic disease. The question of whether either of these practices translates into an increased risk of skin cancer is an important one. Numerous medications have real, distinct and well-elucidated mechanisms that potentiate the development of skin cancer, while with some medications the mechanism for the observed carcinogenesis remains unclear. In this article we will discuss the clinical, mechanistic and epidemiological evidence supporting photochemical genotoxicity and carcinogenesis.

Investigation of the effect of UV irradiation on DNA damage: comparison between skin cancer patients and normal volunteers.

BACKGROUND: Susceptibility to environmental carcinogenesis is the consequence of a complex interplay between intrinsic hereditary factors and actual exposure to potential carcinogenic agents. Exposure to sunlight is the primary etiological agent for basal cell carcinoma (BCC). AIM: The aim of this study was to determine the effects of different ultraviolet (UV) doses on DNA damage in epidermal keratinocytes in vivo and to elucidate if patients with BCC are more susceptible to UV-induced DNA damage in comparison with normal healthy volunteers in response to solar simulator radiation (SSR). MATERIALS AND METHODS: Skin biopsies obtained post-UV irradiation from both normal healthy volunteers and BCC patients were analyzed for DNA damage, using immunohistochemical approach with TDM-2 antibody, which binds specifically to cyclobutane pyrimidine dimmers (CPDs). RESULTS: In both normal volunteers and BCC patients, the peak of CPD-positive cells occurred at 4.5 h post-SSR. There was a statistically significant difference in CPD positivity between BCC patients and normal volunteers, at time points (from 4.5 h to 48 h post-SSR). For a given dose of SSR based on each individual minimal erythema dose (MED), a greater number of CPD-positive cells could be shown. CONCLUSIONS: This study has shown for the first time and in vivo in human volunteers that BCC patients are more susceptible to UV-induced DNA damage in comparison with normal healthy volunteers.

Photoprotective behaviour and sunscreen use: impact on vitamin D levels in cutaneous lupus erythematosus.

BACKGROUND: Sun exposure of the skin, independent of dietary sources, may provide sufficient vitamin D in healthy individuals. A recent study of patients with cutaneous lupus erythematosus concluded that over 70% of them restrict their sun exposure. METHODS: We recruited 52 patients with biopsy-proven cutaneous lupus erythematosus to establish whether they are deficient in 25-hydroxyvitamin D [25(OH)D]. We measured their serum 25(OH)D levels during summer months, investigated the effects of several variables on 25(OH)D levels and assessed the role of vitamin D supplementation. RESULTS: An overall mean 25(OH)D level of 63.03 (+/-23.3) nmol/l was obtained. Significantly low values (<25 nmol/l) were recorded in two (3.8%) patients and concentrations below 75 nmol/l were found in 34 (65.4%) patients. 25(OH)D levels were significantly lower among sun avoiders and daily sunscreen users, while significantly higher values were found among those who took cholecalciferol (vitamin D3) supplements. Low values were recorded among those with renal disease despite supplementation with vitamin D3 in some cases. CONCLUSIONS: We suggest that patients with cutaneous lupus erythematous have suboptimal 25(OH)D levels, which are significantly raised by the addition of at least 400 IU/day of cholecalciferol. We recommend supplementation with an active vitamin D analogue in collaboration with a consultant nephrologist, for the subgroup of patients with renal disease.

Psoriasis of the face and flexures.

Facial and flexural psoriasis may impair the quality of life of psoriatic patients considerably. For the adequate management of psoriasis it is important to pay attention to lesions at these sensitive sites, which require an approach different to that for lesions on other sites in several respects. An extensive literature search was carried out to collect evidence-based data on facial and flexural psoriasis with respect to epidemiology, clinical aspects, pathogenetic factors and various treatments. Subsequently, a panel of experts, the Copenhagen Psoriasis Working Group (CPWG), discussed these aspects and several recommendations were formulated reconciling the evidence-based data. Facial psoriasis occurs in 17-46% of psoriatics and flexural psoriasis is experienced by 6.8-36% of patients with psoriasis. Therefore, psoriasis at these sites cannot be regarded as a rare manifestation. Facial psoriasis is a prognostic marker indicating a poor prognosis of psoriasis. Facial and flexural psoriasis cannot be regarded as distinct disease entities but rather as site variations. The clinical features of facial psoriasis suggest that there are three subtypes: hairline psoriasis, sebo-psoriasis and true facial psoriasis. Otitis externa and ocular manifestations should not be neglected. Evidence that microbiological factors may be relevant to facial and flexural psoriasis is virtually absent. For facial psoriasis the response to UV radiation is variable. At least 5% of psoriatics have photosensitive psoriasis. In these patients photosensitive diseases such as lupus erythematodes and polymorphic light eruption have to be excluded. Based on the literature assessment and working group discussions the CPWG concluded the following. (1) Low-potency topical corticosteroids, vitamin D3 analogues and calcineurin inhibitors are first choice treatments in facial and flexural psoriasis. Evidence for the efficacy of the first two modalities is at level 3 while it is at level 1 for the third one. An individualized approach is indicated; for example, in case of corticosteroid side effects in the past the other two modalities should be selected and in unstable psoriasis prone to irritation, monotherapy with vitamin D3 analogues should be avoided. (2) Antimicrobial treatments are not indicated for facial and flexural psoriasis. (3) Dithranol and tar treatment are not indicated as first-line treatment but only if the first-line options fail. (4) In case topical therapies are not effective, phototherapy and systemic treatments are indicated. (5) For future drug development the combination of vitamin D3 analogues with low strength corticosteroids is recommended.

Association of methylenetetrahydrofolate reductase polymorphism and the risk of squamous cell carcinoma in renal transplant patients.

The relative risk of developing cutaneous squamous cell carcinoma (SCC) is significantly increased after organ transplantation. We investigated the genetic association of SCC in two pathways associated with cancer risks, with the potential for modification by vitamin supplementation. A total of 367 renal transplant recipients (117 with SCC and 250 without any skin cancer) were genotyped for key polymorphisms in the folate pathway (methylene tetrahydrofolate reductase; MTHFR:C677T), and the vitamin D pathway (vitamin D receptor: Intron8G/T;). Individuals carrying the MTHFR 677T allele had a marked increase in risk of SCC (adjusted odds ratio=2.54, P=0.002, after adjustment for age, ender, skin type, sun exposure score, and immunosuppression duration; lower 95% confidence boundary odds ratio of 1.41). In contrast, vitamin D receptor polymorphisms were not significantly associated. Folate-sensitive pathways may play a critical role in the elevated rate of SCC in renal transplant recipients.

Genetic factors associated with skin cancer in renal transplant patients.

BACKGROUND: Non-melanoma skin cancer represents a significant cause of morbidity and mortality among renal transplant recipients. Established risk factors that increase susceptibility to skin cancer after transplantation include skin type, sun exposure and level of immunosuppression. METHODS: A comprehensive literature review was carried out to discuss relevant genetic polymorphism for the development of skin cancer in organ transplant recipients. These include genetic polymorphisms in glutathione S-transferase, interleukin-10, retinoblastoma and p53 genes. We also discuss genetic polymorphisms in the folate pathway, melanocortin 1 receptor and vitamin D receptor recently discovered in our group. RESULTS: No single factor is causative in cutaneous carcinogenesis in transplant recipients. Interactions of some of the above mechanisms with known environmental factors lead to increased risk. CONCLUSION: Polymorphisms in methylenetetrahydrofolate reductase are potentially correctable with folic acid supplementation; however, further evaluation is required in adequately powered prospective clinical trials. Avoidance of known oncogenic environmental factors and genetic risk evaluation may improve outcomes in transplant patients.

Sunscreen use before and after transplantation and assessment of risk factors associated with skin cancer development in renal transplant recipients.

OBJECTIVE: To determine the degree of compliance with sunscreen use among renal transplant recipients before and after transplantation and to determine risk factors associated with skin carcinogenesis. DESIGN: Single-observer study with structured interview using a standardized questionnaire. Medical records and histology reports were examined for details of prior skin cancer. Cox proportional hazards regression was used for analysis of risk factors for developing skin cancer after transplantation. SETTING: Patients attending Beaumont Hospital, the national renal transplantation center in Dublin, Ireland. PATIENTS: The study population comprised 270 patients (182 male and 88 female). MAIN OUTCOME MEASURES: Patients' use of sunscreens before and after transplantation relative to known skin cancer risk factors and subsequent skin carcinogenesis. RESULTS: Prior to transplantation, 68.5% of patients never applied sunscreen on a sunny day compared with 25.9% after transplantation. Patients 50 years or younger were more likely to always apply sunscreen both before and after transplantation (P = .01), as were female patients prior to transplantation (P = .02). Those patients who participated in an outdoor recreation were more likely to subsequently develop nonmelanoma skin cancer (P = .04), as were those older than 50 years (P<.001) and those with a history of 2 or more painful sunburns (P = .03). CONCLUSIONS: Transplant recipients are poorly compliant with the use of sunscreens both before and after transplantation. Compliance is poorest in those groups at higher risk of nonmelanoma skin cancer.

COX-2 expression correlates with microvessel density in non-melanoma skin cancer from renal transplant recipients and immunocompetent individuals.

Angiogenesis, the generation of a new vascular network, is regulated in part by inducers of endothelial cell migration and proliferation, such as cyclooxygenase-2 (COX-2). Microvessel density (MVD) measurement is widely used to quantify angiogenesis in tissue sections of tumors, including cutaneous malignancies. The increasing number of successful renal transplantations worldwide is producing a progressive increase in patients at risk for non-melanoma skin cancers, such as squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and Bowen's disease (BD), and at significantly increased risk for metastatic SCC. The aim of this study was to investigate whether there was any difference in angiogenesis between these tumor types in renal transplant recipients (RTRs) and immunocompetent individuals (ICIs) and whether angiogenesis in these tumors was related to COX-2 expression. The study measured angiogenesis and COX-2 expression in BD, SCC, BCC, and normal skin from both RTRs and ICIs. Vessel counts were performed, and COX-2 immunoexpression was assessed semiquantitatively. The MVD counts differed significantly between normal skin and all tumor types. Significant differences in MVD density were found between all SCCs and BCCs. BCCs from RTRs had significantly greater MVD at the invasive front of the tumor than BCCs from ICIs. Increased COX-2 expression correlated with increased MVD in all tumors examined. These findings indicate a difference in vascular profiles between RTRs and ICIs in BCCs and suggest a relationship between COX-2 and angiogenesis that may provide a possible treatment target for skin tumors in these 2 patient populations.

Investigation of photosensitive disorders.

Investigation of photodermatosis is based primarily on the history and clinical findings, histological, immunological and biochemical findings are variably helpful depending on the clinical picture. Formal testing for photosensitivity may be the only definitive test proving photosensitivity on occasion. This article delineates the important features which allow classification of patients which then enables appropriate treatment.

Diagnosis and management of the erythropoietic porphyrias.

The erythropoietic porphyrias are erythropoietic protoporphyria, and congenital erythropietic porphyria. Diagnosis is made based on clinical manifestations, and their characteristic porphyrin profiles. There are multiple treatment options for these two porphyrias, however, aside from bone marrow transplant for CEP, none is curative.

Sunscreens: safety, efficacy and appropriate use.

Promoting sunscreen use is an integral part of prevention programmes aimed at reducing ultraviolet (UV) radiation-induced skin damage and skin cancers. Protection against both UVB and UVA radiation is advocated. Most sunscreens combine chemical UV absorbing sunscreens and physical inorganic sunscreens, which reflect UV, to provide broad-spectrum protection. Newer triazole and camphor-derivative based sunscreens, also provide broad-spectrum protection and are more cosmetically acceptable than many traditional agents. Currently licensed sunscreen ingredients in common use rarely cause allergic or photoallergic reactions. Vitamin D levels are not significantly affected by regular use of a sunscreen. Sunscreen use reduces both the development of precancerous solar keratosis and the recurrence of squamous cell carcinomas. Sunscreen use early in life may be important in prevention of basal cell carcinomas. Increased melanoma risk is influenced by the behaviour patterns of regular sunscreen users, as opposed to any direct effect of sunscreens. Sun protection factor (SPF) is affected by application density, water resistance and other factors. An adequate SPF for an individual should be balanced to skin phenotype and exposure habits. The correct use of sunscreens should be combined with the avoidance of midday sun and the wearing of protective clothing and glasses, as part of an overall sun protection regimen.

Photoprotection: public campaigns in Ireland and the U.K.

Public education campaigns have been carried out in numerous countries in an effort to halt the rising numbers of skin cancers induced by sun exposure. Though the campaigns undoubtedly increase public awareness of skin cancer, in many countries, such awareness is not translated into alterations in behaviour in the sun. The public continues to rely on sunscreens as the main way of reducing sun exposure. Much education still remains to be translated into behaviour which will reduce skin cancer incidence. Education campaigns need to concentrate on positive aspects with perceived rewards which will then influence behaviour favourably as few people respond to negative messages with no immediate reward.